Pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound

ABSTRACT

To provide a compound usable for treatment of diseases associated with fatty acid amide hydrolase (FAAH), especially for treatment of urinary frequency and urinary incontinence, overactive bladder and/or pain. 
     We have found that a novel pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative and its pharmaceutically acceptable salt has a potent FAAH-inhibitory activity. Further, the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative of the present invention has an excellent effect for increasing an effective bladder capacity, an excellent effect for relieving urinary frequency and an excellent anti-allodynia effect, and is therefore usable for treatment of urinary frequency and urinary incontinence, overactive bladder and/or pain.

This application is a 371 of PCT/JP2006/302698, filed Feb. 16, 2006.

TECHNICAL FIELD

The present invention relates to a pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative or its pharmaceutically acceptable salt, serving as a medicine, especially as a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain having a fatty acid amide hydrolase (hereinafter referred to as FAAH)-inhibitory activity. The present invention also relates to a screening method for an FAAH activity inhibitor serving as a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain; and to a pharmaceutical composition for treatment of urinary frequency and urinary incontinence, for treatment of overactive bladder and/or for treatment of pain that contains the substance obtained according to the screening method of the present invention or contains a substance which inhibits the activity of fatty acid amide hydrolase.

BACKGROUND ART

Fatty acid amide hydrolase (FAAH) is known to hydrolyze endocannabinoid to inactivate it (see Non-Patent References 1 to 4). Endocannabinoid is a generic term for a biological substance that acts on a cannabinoid receptor to exhibit its physiological activity. Typical endocannabinoids are anandamide, palmitoyl ethanolamide, oleamide, 2-arachidonoyl glycerol; and they are known to be hydrolyzed by FAAH to lose their activity. Δ9-tetrahydrocannabinol that is considered as the active ingredient of Cannabis (marijuana) is known to activate a cannabinoid receptor (see Non-Patent Reference 5).

In mammals, two types of cannabinoid receptor CB1 and CB2 have heretofore been known. CB1 is expressed in central and peripheral nervous systems, and when activated, it exhibits its mental action and analgesic action. CB2 is expressed in immune systems, and when activated, it exhibits its antiinflammatory action and analgesic (and antiinflammatory) action.

On the other hand, in a cystitic rat model, a cannabinoid receptor agonist increases the bladder capacity and the urination threshold (Non-Patent Reference 6 and Non-Patent Reference 7); and the side effects of hallucination, delusion, tachycardia, orthostatic hypotension to be observed in administration of a cannabinoid receptor agonist to animals are not observed when an FAAH inhibitor is administered thereto (Non-Patent Reference 8). From these, the FAAH inhibitor is expected as a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain.

As compounds having an FAAH-inhibitory activity, known are compounds capable of serving as analgesic, antianxiety, antiepileptic, antidepressant, antiemetic, cardiovascular agent or antiglaucomatous agent [C1-4 alkyl or polycyclic aromatic ester derivatives of aromatic ring or phenyl-substituted aliphatic hydrocarbon-carbamic acids (Patent Reference 1) and phenyl cyclohexylcarbamate (Patent Reference 2)]. Dioxane-2-alkylcarbamate derivatives, which are compounds having an FAAH-inhibitory activity, are described as a remedy for urinary incontinence, one embodiment of a large number of disorders listed therein (Patent Reference 3). However, Patent Reference 3 does not disclose experimental results to support the remedial effect for treatment of urinary frequency and urinary incontinence and/or for treatment of overactive bladder, not disclosing any suggestion for it. 4-Aminopyridyl piperidine-1-carboxylate, a type of pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylates, is described as an acetylcholine esterase inhibitor (Non-Patent Reference 9); however, the reference describes nothing about the compound to be a remedy for urinary frequency and urinary incontinence and/or a remedy for overactive bladder.

-   Patent Reference 1: WO2003/065989 -   Patent Reference 2: WO2004/033422 -   Patent Reference 3: JP-A 2003-192659 -   Non-Patent Reference 1: Prostaglandins Leukotrienes and Essential     Fatty Acids, (England), 2002, Vol. 66, pp. 143-160 -   Non-Patent Reference 2: British Journal of Pharmacology (England),     2004, Vol. 141, pp. 253-262 -   Non-Patent Reference 3: Nature (England), 1996, Vol. 384, pp. 83-87 -   Non-Patent Reference 4: Biochemical Pharmacology, (USA), 2001, Vol.     62, pp. 517-526 -   Non-Patent Reference 5: Current Medicinal Chemistry (USA), 1999,     Vol. 6, pp. 635-664 -   Non-Patent Reference 6: The Journal of Neuroscience, 2002, Vol. 22,     pp. 7147-7153 -   Non-Patent Reference 7: Pain, 1998, Vol. 76, pp. 189-199 -   Non-Patent Reference 8: Nature Medicine, (England), 2003, Vol. 9,     pp. 76-81 -   Non-Patent Reference 9: Journal of Pharmaceutical Science, 1992,     Vol. 81, pp. 380-385

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain, which are free from or are relieved from cannabinoid-like side effects and a problem of addiction. Other objects are to provide a method for screening for an FAAH activity-inhibiting substance, or that is, a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain; and to provide a pharmaceutical composition for treatment of urinary frequency and urinary incontinence, for treatment of overactive bladder and/or for treatment of pain, which contains the substance obtained according to the screening method of the present invention or a substance capable of inhibiting the activity of a fatty acid amide hydrolase.

Means for Solving the Problems

The present inventors have assiduously studied for producing a compound having an FAAH-inhibitory activity, and as a result, have found out novel pyridyl nitrogen-containing heterocyclic-1-carboxylate derivatives.

In addition, the present inventors have found for the first time that, when a compound having an FAAH-inhibitory activity is administered to a rat suffering from urinary frequency induced by cyclophosphamide, then the effective bladder capacity of the rat increases, and have further found that the compound having an FAAH-inhibitory activity has an excellent therapeutical effect in a pain model rat, therefore providing a screening method for a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain by selecting an FAAH inhibitor, and have thus completed the present invention.

Specifically, the present invention relates to the following:

[1] A pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative of a general formula (I), and its pharmaceutically acceptable salt:

[the symbols in formula (I) have the following meanings: HET¹ represents a 5- to 7-membered non-aromatic nitrogen-containing hetero ring, R¹, R² and R³ are the same or different, each representing

(1) H,

(2) OH,

(3) optionally-esterified carboxyl,

(4) cyano,

(5) lower alkyl-CO—,

(6) oxo (═O),

(7) a formula [R¹⁰¹—(O)m1]m2-[ALK¹ optionally substituted with OH]—(O)n1-,

-   -   (m1 and n1 are the same or different, each indicating 0 or 1,     -   m2 is from 1 to 5,     -   ALK¹ represents lower alkylene, lower alkenylene or lower         alkynylene,     -   R¹⁰¹ represents         -   (i) H,         -   (ii) Ar^(1a) optionally substituted with at least one             substituent selected from the group consisting of:             -   (a) H₂N—,             -   (b) halo,             -   (c) cyano,             -   (d) optionally-esterified carboxyl,             -   (e) a group R^(1011a)R^(1012a)N—CO—,             -   (f) HET²,             -   (g) Ar^(1a) optionally substituted with halo, cyano, OH,                 lower alkyl-O— or lower alkyl,                 -   Ar^(1a) represents aryl,             -   (h) lower alkyl,             -   (j) OH,             -   (k) lower alkyl-O— optionally substituted with Ar^(1a)                 or halo-Ar^(1a),             -   (l) HET²-CO— optionally substituted with halo, Ar^(1a)                 or HETAr^(1a),                 -   HET² represents nitrogen-containing hetero ring,                 -   HETAr^(1a) represents nitrogen-containing                     heteroaryl,             -   (s) HET²-CONR^(1011a)—,             -   (t) H₂NCONH—, and             -   (u) optionally-esterified carboxyl-ALK^(2a),                 -   ALK^(2a) represents lower alkyl or lower alkenyl,         -   (iii) ALK^(2a) optionally substituted with a group             R^(1011a)R^(1012a)N or Ar^(1a),             -   R^(1011a) and R^(1012a) are the same or different, each                 representing                 -   (a) H,                 -   (b) cALK,                 -    cALK represents a cycloalkyl,                 -   (c) ALK^(2a) optionally substituted with halo, cALK,                     OH, lower alkyl-O— or Ar^(1a), or                 -   (d) Ar^(1a)—SO₂— optionally substituted with halo,         -   (iv) HET² optionally substituted with at least one             substituent selected from the group consisting of             -   (a) ALK^(2a) optionally substituted with Ar^(1a) or                 halo-Ar^(1a),             -   (b) Ar^(1a),             -   (c) HETAr^(1a) optionally substituted with lower alkyl,             -   (d) Ar^(1a)—CO— or halo-Ar^(1a)—CO—,         -   (v) cALK optionally substituted with ALK^(2a),         -   or         -   (vi) optionally-esterified carboxyl,         -   (in this, when m2 is from 2 to 5, then [R¹⁰¹—(O)m1]'s may be             the same or different),

(8) a group R¹⁰²-ALK¹⁻N(R¹⁰³)—CO—,

-   -   (R¹⁰² represents         -   (i) H,         -   (ii) cALK,         -   (iii) HETAr^(1a), or         -   (iv) Ar^(1a) optionally substituted with at least one             substituent selected from the group consisting of             -   (a) HO,             -   (b) ALK^(2a)—O—             -   (c) cALK-ALK¹—O—,             -   (d) cALK—Ar^(1a)-ALK¹—O—, and             -   (e) Ar^(1a)-ALK¹—O—,     -   R¹⁰³ represents         -   (i) H,         -   (ii) cALK,         -   (iii) ALK^(2a) optionally substituted with at least one             substituent selected from the group consisting of             -   (a) HET²,             -   (b) Ar^(1a), and             -   (c) halo-Ar^(1a),         -   (iv) HETAr^(1a), or         -   (v) Ar^(1a)—[CO]m1 optionally substituted with at least one             substituent selected from the group consisting of             -   (a) cALK,             -   (b) H₂N,             -   (c) a group R^(1011a)R^(1012a)N—CO—, or             -   (d) ALK^(2a)),

(9) a group R^(104a)R^(105a)N—[CO]m1ALK¹—,

-   -   (R^(104a) and R^(105a) are the same or different, each         representing a group R¹⁰³),

(10) a group R¹⁰⁶-ALK³-L¹-,

-   -   (R¹⁰⁶ represents         -   (i) a group R¹⁰¹—(O)m1-,         -   (ii) a group R^(104a)R^(105a)N—         -   (iii) a group ALK^(2a)—CONH—, or         -   (iv) a group Ar^(1a)—CONH—,     -   ALK³ represents lower alkylene, lower alkenylene or         cycloalkylene,     -   L¹- represents —C(═O)— or —SO₂—),

(11) ALK^(2a)—CONH— optionally substituted with Ar^(1a),

(12) Ar^(1a) substituted with halo,

(13) a group [R¹⁰⁷—(O)m1]m2-Ar²—(O)n1-,

-   -   (Ar² represents arylene,     -   R¹⁰⁷ represents         -   (i) H,         -   (ii) halo,         -   (iii) ALK^(2a) optionally substituted with at least one             substituent selected from the group consisting of             -   (a) HO,             -   (b) cALK,             -   (c) HET²,             -   (d) Ar^(1a) optionally substituted with halo, lower                 alkyl, lower alkyl-O—, a group                 R^(1011a)R^(1012a)N—[CO]p-, cyano or                 optionally-esterified carboxyl,             -   (e) optionally-esterified carboxyl,             -   (f) HET²-[CO]p- optionally substituted with a group                 R^(1011a)R^(1012a)N—[CO]p-, and             -   (g) a group R^(1011a)R^(1012a)N—[CO]p-,                 -   p indicates 0 or 1,         -   (iv) a group R^(1011a)R^(1012a)N—[CO]p-, or         -   (v) a group R^(1011a)R^(1012a)N—[CO]p-Ar^(1a),         -   in this, when m2 is from 2 to 5, then [R¹⁰⁷—(O)m1]'s may be             the same or different, and further the group [R¹⁰⁷—(O)m1]m2             may be methylenedioxy to form a ring),

(14) a group [R¹⁰⁷—(O)m1]m2-Ar²—N(R¹⁰³)—CO—,

-   -   (in this, when m2 is from 2 to 5, then [R¹⁰⁷—(O)m1]'s may be the         same or different),

(15) a group [R^(1011a)R^(1012a)N—[CO]m1]m2-Ar²—(O)n1-,

-   -   (in this, when m2 is from 2 to 5, then         [R^(1011a)R^(1012a)N—[CO]m1]'s may be the same or different),

(16) a group [R¹⁰⁸]m2-Ar²-L²-,

-   -   [R¹⁰⁸ represents         -   (i) H,         -   (ii) halo,         -   (iii) HO,         -   (iv) cALK-O—,         -   (v) a group R¹⁰⁹-ALK¹—(O)m1-,             -   (R¹⁰⁹ represents                 -   (a) H,                 -   (b) cALK,                 -   (c) Ar^(1a) optionally substituted with at least one                     substituent selected from the group consisting of                 -    (1′) halo,                 -    (2′) cyano,                 -    (3′) NO₂,                 -    (4′) ALK^(2a) optionally substituted with halo,                 -    (5′) HO,                 -    (6′) ALK^(2a)—O— optionally substituted with halo,                 -    (7′) optionally-esterified carboxyl, or                 -    (8′) a group R^(104a)R^(105a)N—,                 -   (d) HETAr^(1a), or                 -   (e) a group R^(104a)R^(105a)N—[CO]m1-),         -   (vi) a group R¹⁰¹³R¹⁰¹⁴N—,             -   R¹⁰¹³ and R¹⁰¹⁴ are the same or different, each                 representing                 -   (i) H,                 -   (ii) ALK^(2a),                 -   (iii) cALK-ALK¹—, or                 -   (iv) Ar^(1a)-ALK¹— optionally substituted with at                     least one substituent selected from the group                     consisting of                 -    (1′) halo,                 -    (2′) cyano,                 -    (3′) ALK^(2a) optionally substituted with halo,                 -    (4′) ALK^(2a)—O— optionally substituted with halo,         -   (vii) HET²-(O)m1- optionally substituted with lower alkyl,     -   L² represents —CO— or —S(O)_(q)—,         -   q indicates 0, 1 or 2,     -   in this, when m2 is from 2 to 5, then [R¹⁰⁸]'s may be the same         or different],

(17) a group [R¹⁰¹]m2-Ar²—CONH—,

-   -   (in this, when m2 is from 2 to 5, then [R¹⁰¹]'s may be the same         or different),

(18) a group [R¹¹¹]m2-HETAr²—(O)m1-,

-   -   (R¹¹¹ represents         -   (i) H,         -   (ii) halo,         -   (iii) oxo (═O), or         -   (iv) a group R^(103a)—(O)n1-,             -   R^(103a) represents                 -   (i) H,                 -   (ii) cALK,                 -   (iii) ALK^(2a) optionally substituted with at least                     one substituent selected from the group consisting                     of                 -    (a) HET²,                 -    (b) Ar^(1a),                 -    (c) cALK and                 -    (d) halo-Ar^(1a),                 -   (iv) HETAr^(1a), or                 -   (v) Ar^(1a) optionally substituted with at least one                     substituent selected from the group consisting                     of (a) cALK, (b) H₂N, and (c) a group                     R^(1011a)R^(1012a)N—CO—,                 -    HETAr² represents nitrogen-containing                     heteroarylene,                 -    in this, when m2 is from 2 to 5, then [R¹¹¹]'s may                     be the same or different),

(19) a formula [R¹¹²]m2-HETAr²—N(R¹⁰³)—CO—,

-   -   (R¹¹² represents         -   (i) H,         -   (ii) cALK,         -   (iii) ALK^(2a), or         -   (iv) Ar^(1a) optionally substituted with at least one             substituent selected from the group consisting of             -   (a) halo,             -   (b) HO,             -   (c) ALK^(2a)—O—, and             -   (d) Ar^(1a)-ALK¹—O—,         -   in this, when m2 is from 2 to 5, then [R¹¹²]'s may be the             same or different,

(20) a formula [R¹⁰⁸]m2-HETAr²-L²-,

-   -   (in this, when m2 is from 2 to 5, then [R¹⁰⁸]'s may be the same         or different), provided that, when any one group of R¹, R² and         R³ is a group [R¹¹¹]m2-HETAr²—(O)m1- and when m1 is 0, then the         remaining groups of R¹, R² and R³ are H;         R⁴, R⁵, R⁶ and R⁷ are the same or different, each representing

(1) H,

(2) halo,

(3) optionally-esterified carboxyl,

(4) HO,

(5) a group R¹¹³-ALK⁴—(O)m3-,

-   -   (ALK⁴ represents lower alkylene, lower alkenylene, or lower         alkynylene, m3 indicates 0 or 1,     -   R¹¹³ represents         -   (i) H,         -   (ii) HO,         -   (iii) lower alkyl-O— optionally substituted with             optionally-esterified carboxyl,         -   (iv) optionally-esterified carboxyl,         -   (v) lower alkyl-CO—O—, or         -   (vi) a group R^(104b)R^(105b)N—[CO]m3-(R^(104b) and R^(105b)             are the same or different, each representing a group R¹⁰³),

(6) R¹¹⁴R¹¹⁵N(R¹¹⁴ and R¹¹⁵ are the same or different, each representing

-   -   (i) H, or     -   (ii) ALK^(2b) optionally substituted with a group         R^(104b)R^(105b)N,         -   ALK^(2b) represents lower alkyl or lower alkenyl),

(7) a group R¹¹⁶-(ALK⁴)n2-N(R¹¹⁷)—CO—,

-   -   (n2 indicates 0 or 1,     -   R¹¹⁶ represents         -   (i) H,         -   (ii) HO,         -   (iii) lower alkyl-O—,         -   (iv) optionally-esterified carboxyl,         -   (v) a group R^(104b)R^(105b)N—[CO]m3-,         -   (vi) Ar^(1b) optionally substituted with (a) OH or (b)             ALK^(2b)—O—,             -   Ar^(1b) represents aryl,         -   (vii) HET³ optionally substituted with a group             R^(104b)R^(105b)N—[CO]m3- or optionally-esterified carboxyl,             -   HET³ represents nitrogen-containing hetero ring,         -   (viii) Ar^(1b) optionally substituted with a group             R^(104b)R^(105b)N—[CO]m3-, or         -   (ix) SO₃H),     -   R¹¹⁷ represents (i) H or (ii) ALK^(2b) optionally substituted         with Ar^(1b),

(8) Ar^(1b) optionally substituted with at least one substituent selected from the group consisting of optionally-esterified carboxyl and a group R^(1011b)R^(1012b)N—[(CO)]m3-,

-   -   R^(1011b) and R^(1012b) are the same or different, each         representing         -   (i) H,         -   (ii) cALK,         -   (iii) ALK^(2b) optionally substituted with halo, cALK, OH,             lower alkyl-O— or Ar^(1b), or         -   (iv) Ar^(1b)—SO₂— optionally substituted with halo,

(9) HET³ optionally substituted with optionally-esterified carboxyl,

(10) HET³-CO— optionally substituted with at least one substituent selected from the group consisting of ALK^(2b) and a group R^(104b)R^(105b)N—[CO]m3-, or

(11) cyano,

provided that 4-aminopyridin-3-yl piperidine-1-carboxylate is excluded—the same shall be applied hereinunder].

[2] The compound of [1], represented by a general formula (II):

[in formula (II), R¹ to R⁷ have the same meanings as in [1], T represents CH₂, NH, NHCH₂ or O, and this includes a case where the hydrogen in T is substituted with R¹ to R³—the same shall be applied hereinunder]. [3] The compound of [2], wherein R¹ to R³ are the same or different, each representing a group [R¹⁰¹—(O)m1]m2-[ALK¹ optionally substituted with OH]—(O)n1-, a group R¹⁰²-ALK¹—N(R¹⁰³)—CO—, a group R¹⁰⁶-ALK³-L¹-, a group [R¹⁰⁷—(O)m1]m2-Ar²—(O)n1-, a group [R¹⁰⁷—(O)m1]m2-Ar²—N(R¹⁰³)—CO—, or a group [R¹⁰⁸]m2-Ar²-L²-. [4] A pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative of a general formula (III) and its pharmaceutically acceptable salt:

[the symbols in formula (III) have the following meanings: ring A represents benzene ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, or 5- to 7-membered nitrogen-containing hetero ring; L represents single bond, lower alkylene, lower alkenylene, —N(R¹⁵)—C(═O)—, —C(═O)—N(R¹⁵)—, -(lower alkenylene)-C(═O)—, —O—, or —C(═O)—, R¹⁵ represents H, or lower alkyl, X represents CH, or N, R⁸ to R¹⁰ are the same or different, each representing

-   -   a group selected from the following group G,     -   aryl optionally substituted with the same or different groups         selected from the following group G,     -   nitrogen-containing heteroaryl optionally substituted with the         same or different groups selected from the following group G,     -   R¹⁶-(lower alkylene)-O—,     -   R¹⁶-(lower alkylene)-N(R¹⁵)—, or     -   R¹⁷R¹⁸N—C(═O)—,         R¹⁶ represents     -   aryl optionally substituted with the same or different groups         selected from the following group G,     -   nitrogen-containing heteroaryl optionally substituted with the         same or different groups selected from the following group G, or     -   3- to 8-membered cycloalkyl,         R¹⁷ and R¹⁸— are the same or different, each representing H,         lower alkyl, or 3- to 8-membered cycloalkyl,         (further, R¹⁷ and R¹⁸ may form, together with the N atom bonding         thereto, 3- to 8-membered nitrogen-containing hetero ring),         the group G includes H, halo, —CN, —CF₃, lower alkyl, or         —O-lower alkyl,         R¹¹ represents H, lower alkyl, or oxo (═O),         R¹² to R¹⁴ are the same or different, each representing H, lower         alkyl, —C(═O)—O-(lower alkyl), —CO₂H, or —CONH₂].         [5] The compound of [4], wherein the ring A is benzene ring,         cyclohexane ring, piperidine ring, or piperazine ring.         [6] The compound of [5], wherein R⁹, R¹⁰, R¹¹, R¹² and R¹³ are         H.         [7] A pyridyl non-aromatic nitrogen-containing         heterocyclic-1-carboxylate of a general formula (IV) and its         pharmaceutically acceptable salt:

[the symbols in formula (IV) have the following meanings: ring A¹ represents benzene ring, piperidine ring or piperazine ring; L¹ represents lower alkylene, lower alkenylene, —N(R¹⁵)—C(═O)—, or —O—; R¹⁵ represents H, or lower alkyl, R¹⁹ represents

-   -   a group selected from the following group G,     -   nitrogen-containing heteroaryl optionally substituted with the         same or different groups selected from the following group G,     -   R¹⁶-(lower alkylene)-O—, or R¹⁷R¹⁸N—C(═O)—,         R¹⁶ represents     -   aryl optionally substituted with the same or different groups         selected from the following group G,     -   nitrogen-containing heteroaryl optionally substituted with the         same or different groups selected from the following group G, or     -   3- to 8-membered cycloalkyl,         R¹⁷ and R¹⁸ are the same or different, each representing H, or         lower alkyl,         (further, R¹⁷ and R¹⁸ may form, together with the N atom bonding         thereto, 5- or 6-membered nitrogen-containing hetero ring),         the group G includes H, halo, —CN, —CF₃, lower alkyl, or         —O-lower alkyl,         R²⁰ represents H, —C(═O)—O-(lower alkyl), —CO₂H, or —CONH₂].         [8] A pyridyl non-aromatic nitrogen-containing         heterocyclic-1-carboxylate of a general formula (V) and its         pharmaceutically acceptable salt:

[the symbols in formula (V) have the following meanings: L² represents lower alkylene, lower alkenylene, or -(lower alkenylene)-C(═O)—, R²¹ represents H, halo, —CN, —CF₃, lower alkyl, or —O-lower alkyl, R²² represents H, —C(═O)—O-(lower alkyl), —CO₂H or —CONH₂]. [9] The compound of [1] selected from the following group:

-   pyridin-3-yl     4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate, -   5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}nicotinic     acid, -   5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinic acid, -   5-[({4-[4-(2-cyclohexylethoxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic     acid, -   5-[({4-[(E)-2-phenylvinyl]piperidin-1-yl}carbonyl)oxy]nicotinic     acid, -   5-{[(4-[3-[1-(6-methylpyridin-2-yl)piperidin-4-yl]propyl}piperidin-1-yl)carbonyl]oxy}nicotinic     acid, -   5-(aminocarbonyl)pyridin-3-yl     4-{2-[3-(aminocarbonyl)phenyl]ethyl}piperidine-1-carboxylate, -   5-(aminocarbonyl)pyridin-3-yl     4-(2-{3-[(dimethylamino)carbonyl]phenyl}ethyl)piperidine-1-carboxylate, -   5-(aminocarbonyl)pyridin-3-yl     4-{2-[3-(piperidin-1-ylcarbonyl)phenyl]ethyl}piperidine-1-carboxylate, -   5-(aminocarbonyl)pyridin-3-yl     4-{2-[3-(pyrrolidin-1-ylcarbonyl)phenyl]ethyl}piperidine-1-carboxylate, -   pyridin-3-yl 4-[(2E)-3-phenylprop-2-enoyl]piperazine-1-carboxylate, -   pyridin-3-yl 4-(anilinocarbonyl)piperidine-1-carboxylate, -   5-(aminocarbonyl)pyridin-3-yl     4-(2-phenylethyl)piperidine-1-carboxylate, pyridin-3-yl     4-(2-phenylethyl)piperazine-1-carboxylate, -   5-(methoxycarbonyl)pyridin-3-yl     4-(2-phenylethyl)piperazine-1-carboxylate, -   5-(aminocarbonyl)pyridin-3-yl     4-[2-(3-fluorophenyl)ethyl]piperidine-1-carboxylate, -   5-(aminocarbonyl)pyridin-3-yl     4-[2-(3-cyanophenyl)ethyl]piperidine-1-carboxylate.     [10] A pharmaceutical composition comprising the compound of [1] as     an active ingredient thereof.     [11] The pharmaceutical composition of [10], which is an FAAH     inhibitor.     [12] The pharmaceutical composition of [10], which is a medicament     for treatment of urinary frequency, urinary incontinence and/or     overactive bladder.     [13] The pharmaceutical composition of [10], which is a medicament     for treatment of pain.     [14] Use of the compound of [1] for the manufacture of an FAAH     inhibitor or a medicament for treatment of urinary frequency,     urinary incontinence and/or overactive bladder.     [15] Use of the compound of [1] for the manufacture of an FAAH     inhibitor or a medicament for treatment of pain.     [16] A method for treating urinary frequency, urinary incontinence     and/or overactive bladder, comprising administering a     therapeutically effective amount of the compound of [1] to a     patient.     [17] A method for treating pain, comprising administering a     therapeutically effective amount of the compound of [1] to a     patient.     [18] A screening method for a remedy for urinary frequency and     urinary incontinence, a remedy for overactive bladder and/or a     remedy for pain, comprising (1) a step of contacting a test     substance with a polypeptide, which contains (a) an amino acid     sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ     ID NO:8, (b) an amino acid sequence derived from the amino acid     sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ     ID NO:8 through deletion, substitution and/or insertion of from 1 to     10 amino acids therein, (c) an amino acid sequence having a homology     of at least 70% to the amino acid sequence represented by SEQ ID     NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, or (d) an amino acid     sequence of the entire amino acid sequence encoded by a     polynucleotide represented by SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5     or SEQ ID NO:7 or by a polynucleotide capable of hybridizing with     its complementary sequence under a stringent condition, or its part     not having at least the transmembrane region-containing amino     terminal region thereof, and which may hydrolyze a substrate, (2) a     step of analyzing the polypeptide for its activity change, and (3) a     step of selecting a substance capable of inhibiting the polypeptide     activity,     (wherein the “substrate” with which FAAH or functional FAAH is     contacted may be any and every endocannabinoid capable of being     hydrolyzed by FAAH or functional FAAH; and concretely, it includes     anandamide, palmitoylethanolamide, 2-arachidonoyl glycerol, and     oleamide; and the substrate labeled with ³H or ¹⁴C, as well as a     mixture of the labeled substrate and the unlabeled substrate may be     used—the same shall be applied hereinunder).     [19] A screening method for a remedy for urinary frequency and     urinary incontinence, a remedy for overactive bladder and/or a     remedy for pain, comprising (1) a step of contacting a test     substance with a polypeptide, which contains (a) an amino acid     sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ     ID NO:8, (b) an amino acid sequence derived from the amino acid     sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ     ID NO:8 through deletion, substitution and/or insertion of from 1 to     10 amino acids therein, (c) an amino acid sequence having a homology     of at least 70% to the amino acid sequence represented by SEQ ID     NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, or (d) an amino acid     sequence of the entire amino acid sequence encoded by a     polynucleotide represented by SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5     or SEQ ID NO:7 or by a polynucleotide capable of hybridizing with     its complementary sequence under a stringent condition, or its part     not having at least the transmembrane region-containing amino     terminal region thereof, and which may hydrolyze a substrate, in the     presence of a substrate of the polypeptide, (2) a step of measuring     the amount of the hydrolyzed product converted from the substrate,     and (3) a step of selecting a substance capable of inhibiting the     hydrolysis of the substrate.     [20] A screening method for a remedy for urinary frequency and     urinary incontinence, a remedy for overactive bladder and/or a     remedy for pain, comprising (1) a step of contacting a test     substance with a cell or a tissue expressing a polypeptide, which     contains (a) an amino acid sequence represented by SEQ ID NO:2, SEQ     ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, (b) an amino acid sequence     derived from the amino acid sequence represented by SEQ ID NO:2, SEQ     ID NO:4, SEQ ID NO:6 or SEQ ID NO:8 through deletion, substitution     and/or insertion of from 1 to 10 amino acids therein, (c) an amino     acid sequence having a homology of at least 70% to the amino acid     sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ     ID NO:8, or (d) an amino acid sequence of the entire amino acid     sequence encoded by a polynucleotide represented by SEQ ID NO:1, SEQ     ID NO:3, SEQ ID NO:5 or SEQ ID NO:7 or by a polynucleotide capable     of hybridizing with its complementary sequence under a stringent     condition, or its part not having at least the transmembrane     region-containing amino terminal region thereof, and which may     hydrolyze a substrate, or with a lysate or a homogenate of the cell     or the tissue, in the presence of a substrate of the     polypeptide, (2) a step of measuring the amount of the hydrolyzed     product converted from the substrate, and (3) a step of selecting a     substance capable of inhibiting the hydrolysis of the substrate.     [21] A screening method for a remedy for urinary frequency and     urinary incontinence, a remedy for overactive bladder and/or a     remedy for pain, comprising (1) a step of contacting a test     substance with a fatty acid amide hydrolase, (2) a step of analyzing     the enzyme for its activity change, and (3) a step of selecting a     substance capable of inhibiting the activity of the enzyme.     Outcomes of the Invention

The pharmacological tests of Examples 438 to Example 442 have confirmed the effectiveness of the compounds of the present invention. For example, typical compounds shown in Table 64 have an excellent FAAH-inhibitory effect; typical compounds shown in Example 441 are useful as a remedy for urinary frequency and urinary incontinence, and a remedy for overactive bladder; and typical compounds shown in Example 442 are useful as a remedy for pain. In addition, the compounds of the present invention are highly stable in aqueous solutions, and have excellent properties as medicines.

The invention described in Patent Reference 2 is useful as analgesic, antianxiety, antiepileptic, antidepressant, antiemetic, cardiovascular agent or antiglaucomatous agent; however, the present inventors have found that the present invention is useful for a remedy for urinary frequency and urinary incontinence and/or a remedy for overactive bladder, differing from Patent Reference 2. Further, the compounds of the present invention have an excellent FAAH-inhibitory effect, and are therefore useful for remedies for (1) neuropsychiatric disorders (e.g., anxiety, depression, epilepsy), (2) brain disorders, neurodegenerative disorders (e.g., head injury, cerebral ischemia, dementia), (3) immunological and inflammatory diseases, (4) vomiting, (5) eating disorders, (6) irritable bowel syndrome, ulcerative colitis, (7) hypertension, (8) glaucoma, or (9) sleep disorders. In addition, the compounds are free from or are relieved from cannabinoid-like side effects and a problem of addiction.

Further, according to the screening method of the present invention, a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain that are free from or are relieved from cannabinoid-like side effects and a problem of addiction can be selected on the basis of inhibition of FAAH activity. The substances obtained according to the screening method and the FAAH activity-inhibitory substances may produce pharmaceutical compositions useful for treatment of urinary frequency and urinary incontinence, for treatment of overactive bladder and/or for treatment of pain.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in detail hereinunder.

The compounds of the present invention are described in detail hereinunder.

DEFINITIONS

Unless otherwise specifically indicated, the term “lower” in the definition of the structural formulae in this description means a linear or branched carbon chain having from 1 to 6 carbon atoms.

“Lower alkyl” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl; preferably methyl, ethyl, propyl, butyl, tert-butyl.

“Lower alkenyl” means an aliphatic hydrocarbon group having at least one double bond, including, for example, vinyl, propenyl, allyl, isopropenyl, 1,3-butadienyl, hexenyl.

“Cycloalkyl” means a mono- to tri-cyclic aliphatic saturated hydrocarbon ring group having from 3 to 14 carbon atoms, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloheptyl, bicyclooctyl, tricyclododecanyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

“Aryl” means a mono- to tri-cyclic aromatic hydrocarbon ring group having from 6 to 14 carbon atoms, in which the phenyl may be condensed with cycloalkyl. For example, it includes phenyl, indenyl, naphthyl, anthryl, phenanthryl, indanyl, tetrahydronaphthyl, preferably phenyl, naphthyl.

“Heterocyclic” means a 4- to 16-membered, monocyclic, bicyclic or tricyclic, saturated or unsaturated ring having from 1 to 4 hetero atoms selected from N, S and O. The heterocyclic group may be crosslinked or spiro-structured. The unsaturated ring includes an aromatic ring (heteroaryl) and a non-aromatic ring. The monocyclic group includes azetidinyl, oxetanyl, pyrrolidinyl, 1,3-dioxolanyl, pyrazolidinyl, piperazinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, triazolyl, thiadiazolyl, pyridazinyl, oxadiazolyl, tetrazolyl; the bicyclic group includes indolyl, isoindolyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzimidazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, decahydroisoquinolyl, quinoxalinyl; the tricyclic group includes carbazolyl, acridinyl, phenothiazinyl. The crosslinked heterocyclic group includes quinuclidinyl, 2,5-diazabicyclo[2.2.1]heptyl, 8-azabicyclo[3.2.1]octyl, 7-azabicyclo[2.2.1]heptyl. The spiro-structured heterocyclic group includes 1,4-dioxa-8-azaspiro[4,5]decanyl.

“Nitrogen-containing heteroaryl” means a 4- to 10-membered, mono- or bi-cyclic aromatic nitrogen-containing heteroaryl, having from 1 to 4 nitrogen atoms of the above-mentioned heterocyclic group. It includes, for example, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, quinolyl, isoquinolyl, quinoxalinyl, preferably imidazolyl, thiazolyl, pyridyl, benzimidazolyl, quinolyl.

“Nitrogen-containing saturated heterocyclic group” means a 3- to 10-membered, mono- or bi-cyclic nitrogen-containing heterocycloalkyl group, having from 1 to 3 nitrogen atoms of the above-mentioned heterocyclic group. It includes, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, hexahydroazepinyl, 1,4-diazepinyl, 1,4-oxazepinyl, quinuclidinyl, 2,5-diazabicyclo[2.2.1]heptyl, azabicyclooctyl (e.g., azabicyclo[3.2.1]octyl), diazabicyclooctyl, azabicyclononyl, azabicyclodecanyl, 1,4-dioxa-8-azaspiro[4,5]decanyl, preferably pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, hexahydroazepinyl, 1,4-diazepinyl, 1,4-oxazepinyl, quinuclidinyl, 2,5-diazabicyclo[2.2.1]heptyl, azabicyclo[3.2.1]octyl.

“Nitrogen-containing hetero ring” means the above-mentioned nitrogen-containing heteroaryl group, the above-mentioned nitrogen-containing saturated heterocyclic group, or a condensed group of nitrogen-containing heteroaryl and nitrogen-containing heterocycloalkyl. Preferably, it is pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, hexahydroazepinyl, azabicyclo[3.2.1]octyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, imidazolyl, pyridyl, quinolyl.

“Non-aromatic nitrogen-containing hetero ring” means a nitrogen-containing saturated heterocyclic group and an unsaturated nitrogen-containing heterocyclic group except the nitrogen-containing heteroaryl of the above-mentioned nitrogen-containing heterocyclic group. Preferably, it is a 5- to 7-membered non-aromatic nitrogen-containing heterocyclic group.

“Lower alkylene”, “lower alkenylene”, “cycloalkylene”, “arylene” and “nitrogen-containing heteroarylene” are divalent groups derived from the above-mentioned lower alkyl, lower alkenyl, cycloalkyl, aryl and nitrogen-containing heteroaryl, by removing any one hydrogen atom from them.

“Esterified carboxyl” means lower alkyl-O—CO—, aryl-lower alkyl-O—CO—, or —H₂N—CO-aryl-lower alkyl-O—CO—.

“Halo” means a halogen group, concretely including fluoro, chloro, bromo, iodo, preferably fluoro, chloro.

“Optionally substituted” means “unsubstituted” or “substituted with the same or different, 1 to 5 substituents”.

Depending on the type of the substituent therein, the compound (I) of the present invention may have optical isomers (optically-active isomers, diastereomers) or geometric isomers. Accordingly, the compound (I) of the present invention includes mixtures or isolated compounds of these optical isomers or geometric isomers.

The compound (I) of the present invention may form pharmaceutically acceptable salts such as acid-addition salts or salts with bases. For example, the salts includes acid addition salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; or an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid; as well as salts with an inorganic base such as sodium, potassium, magnesium, calcium, aluminium; or an organic base such as methylamine, ethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine, lysine, ornithine. Further, the compound (I) or its pharmaceutically acceptable salt of the present invention may form hydrates, solvates with ethanol or the like, and crystalline polymorphs.

Further, the compound (I) of the present invention includes all compounds capable of being metabolized in living bodies to be converted into the compound (I) or its pharmaceutically acceptable salt of the present invention, that is, prodrugs. The group to form prodrugs of the compound (I) of the present invention includes those described in Prog. Med., 5:2157-2161 (1985), and those described in “PHARMACEUTICAL RESEARCH and DEVELOPMENT”, VOLUME 7 Drug Design, pp. 163-198 by Hirokawa Publishing, 1990. Concretely, they are groups capable of being converted into primary amine or secondary amine, or HO—, HO—CO— or the like in the present invention through hydrolysis or solvolysis or under a physiological condition. Prodrugs of HO— are, for example, optionally-substituted lower alkyl-CO—O—, optionally-substituted aryl-CO—O—, optionally-substituted heteroaryl-CO—O—, RO—CO-optionally-substituted lower alkylene-CO—O— (R means H— or lower alkyl—the same shall be applied hereinunder), RO—CO-optionally-substituted lower alkenylene-CO—O—, RO—CO-lower alkylene-O-lower alkylene-CO—O—, RO—CO—CO—O—, ROS(═O)₂-optionally-substituted lower alkenylene-CO—O—, phthalidyl-O—, 5-methyl-1,3-dioxolen-2-on-4-yl-methyloxy.

“Urinary frequency” as referred to in this description indicates a condition where the urination frequency has increased over a normal range. “Urinary incontinence” means a involuntary urination that is problematic in a social and sanitary life.

“Overactive bladder” as referred to in this description indicates a syndrome to be diagnosed by a subjective symptom such as urinary frequency or urgency (Neurourology and Urodynamics, USA, 2002, Vol. 21, pp. 167-178). The pathogenic cause includes, for example, neuropathy (for example, caused by neurogenic bladder, cerebral infarction), lower urinary tract obstruction (e.g., benign prostatic hypertrophy) and aging; and as the pathogenic mechanism common to these, hyperactivity of capsaicin-sensitive afferent neuron.

Overactive bladder may be treated by relieving the condition of urinary frequency, urinary incontinence and urgency. This is obvious, for example, from the fact that administration of an anticholinergic agent, oxybutynin hydrochloride (Japan Standard Product Classification Number 87259; by Aventis Pharma) to a patient suffering from overactive bladder, at a dose of from 2 to 3 mg/once and three times a day may relieve the condition of urinary frequency, urinary incontinence and urgency, and the administration is therefore effective for treatment of overactive bladder.

The presence of the effect for treatment of urinary frequency and urinary incontinence and/or the effect for treatment of overactive bladder may be confirmed by methods known to those skilled in the art or by modified methods from them. For example, a pathologic model induced by administration of from 50 to 200 mg of cyclophosphamide (CPA) to rat, guinea pig, dog or the like is frequently used in this technical field (Ozawa et al., The Journal of Urology, Vol. 162, pp. 2211-2216, 1999; Boucher et al., The Journal of Urology, Vol. 164, pp. 203-208, 2000). This is a pathologic model that accompanies hemorrhagic cystitis, and since capsaicin-sensitive afferent neuron participates in the pathogenic mechanism of urinary frequency, it may be considered that this model may be a suitable pathologic model for various types of overactive bladder including neuropathic bladder (Carlo Alberto Maggi et al., Journal of the Autonomic Nervous System, Vol. 38, pp. 201-208, 1992). A urinary frequency condition may be confirmed by the decrease in the effective bladder capacity. To the pathologic model animal, an effective dose of a pharmaceutical composition is administered orally, intraperitoneally or intravenously, once or plural times; and when the effective bladder capacity of the animal has increased, then the effect of the pharmaceutical composition for treatment of urinary frequency and urinary incontinence and/or for treatment of overactive bladder may be confirmed.

“Pain” as referred to in this description is a generic term for neuropathic pain, nociceptive pain and inflammatory pain, of which “neuropathic pain” means pain caused by peripheral or central nervous system dysfunction and includes diabetic neuropathic pain, cancer pain, trigeminal neuralgia, phantom pain, postherpetic pain and thalamic pain. The essential clinical symptom of neuropathic pain includes pain as if clutched, pain as if scorched, hyperalgesia and allodynia.

Nonsteroidal antiinflammatory drugs and narcotic analgesics such as morphine that are ordinary analgesics are known to be weakly effective for neuropathic pain. In a medical site, an antiepileptic such as gabapentin, and an antiarrhythmic such as mexiletine are used for pain relief, but their analgesic potency is not sufficient.

The presence of the effect for treatment of neuropathic pain may be confirmed by methods known to those skilled in the art or by modified methods from them. For example, using an L5/L6 spinal nerve ligated rat that is produced according to partial modification of a Kim and Chung's method (Pain, Vol. 50, pp. 355-363, 1992), the ameliorating effect of a compound for significant reduction in the response threshold to tactile stimulation (allodynia) is evaluated, and based on it, the effect of the tested compound for treatment of neuropathic pain may be confirmed.

The compound of the present invention includes those effective for urinary frequency and urinary incontinence as well as overactive bladder; those effective for pain, especially for neuropathic pain; and those effective for both the two.

[Production Methods]

The compound and its pharmaceutically acceptable salt of the present invention can be produced by applying various known production methods, utilizing the characteristics based on its basic skeleton of the compound or the type of the substituent therein.

Depending on the type of a functional group in the compound, it may often be effective in point of its production technology to substitute the functional group with a suitable protective group (capable of being readily converted into the functional group) in a stage of its starting material or intermediate. The functional group includes, for example, an amino group, a hydroxyl group and a carboxyl group; and their protective groups are, for example, those described in “Protective Groups in Organic Synthesis (2nd Ed)” by Greene & Wuts. These may be suitably selected and used depending on the reaction conditions.

In this method, the protective groups is removed if necessary after it has been introduced and the reaction carried out, in order to produce the desired compound.

Typical production methods for the compounds of the present invention and their intermediates are described below.

(The abbreviations given in the following description are as follows:

-   -   DMF: N,N-dimethylformamide,     -   DMSO: dimethylsulfoxide,     -   THF: tetrahydrofuran,     -   TFA: trifluoroacetic acid,     -   Tol: toluene,     -   EtOAc: ethyl acetate,     -   DCE: 1,2-dichloroethane,     -   TEA: triethylamine)

Typical production methods for the compounds of the present invention described below, to which, however, the present invention should not be limited.

In case where a similar substituent exists in a site of the compound of the present invention except that in the reaction formula in the production method for the compound, the compound that is encompassed within the scope of the present invention may be readily produced through substituent modification.

Production Method 1 (Carbamate Formation):

(In the formula, X represents a leaving group advantageous to the reaction, and the same shall be applied hereinunder.)

This reaction is for esterification of a ketone derivative of a general formula (VI) and a reaction-corresponding amount of a hydroxypyridine derivative of a general formula (VII), in a solvent inert to the reaction, with stirring with cooling or at room temperature or with heating. The leaving group X includes, for example, a halogen atom, a lower alkoxy group, a phenoxy group, an imidazolyl group. The inert solvent includes, for example, DMF, dimethylacetamide, THF, dioxane, dimethoxyethane, diethoxyethane, benzene, Tol, xylene and their mixed solvents. For promoting the reaction, a base (e.g., sodium, sodium hydride, sodium methoxide, sodium ethoxide) is preferably added to the reaction mixture.

Production Method 2 (Carbamate Formation):

This reaction is conducted by stirring a nitrogen-containing heterocyclic compound of a general formula (VIII) and a reaction-corresponding amount of a pyridine derivative of a general formula (IX) in a solvent inert to the reaction, with cooling or at room temperature or with heating. For promoting the reaction, a base (e.g., sodium, sodium hydride, sodium methoxide, sodium ethoxide, TEA, pyridine) is preferably added to the reaction mixture.

Production Method 3 (Hydrolysis):

A compound (1-3) of the present invention having a carboxyl group can be obtained through hydrolysis of the corresponding compound having an esterified carboxyl group, for example, according to deprotection described in “Protective Groups in Organic Synthesis (2nd Ed)” by Greene & Wuts.

(In the formula, the group ROCO— means an esterified carboxyl group, and the same shall be applied hereinunder.) Production Method 4 (Amidation):

The compound (I-3) or the compound where R¹ is a carboxylic acid may react with an amine, and the compound where R¹ is an amine may react with a carboxylic acid, thereby various amide compounds can be obtained. When the nitrogen-containing heterocyclic compound is piperidine, then it may be reacted with a carboxylic acid or a sulfonic acid compound or their reactive derivative to produce various types of amide compounds. The reaction may be conducted in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), 1,1′-carbonylbis-1H-imidazole (CDI)) and optionally further in the presence of an additive (e.g., N-hydroxysuccinimide (HONSu) 1-hydroxybenzotriazole (HOBt), dimethylaminopyridine (DMAP)). The reactive derivative of the carboxylic acid or the sulfonic acid compound includes acid halides, acid anhydrides, active esters. The reaction may also be conducted, for example, according to the methods described in “Jikken Kagaku koza (Courses in Experimental Chemistry, 4th Ed)”, Vol. 22, edited by the Chemical Society of Japan, Maruzen, 1992.

Production Method 5 (Coupling Reaction):

(In the formula, the symbols have the following meanings. X represents halogen or —O—SO₂CF₃, and Y represents —B(OH)₂, dialkylboron, dialkoxyboron or trialkyltin. X may be —B(OH)₂, dialkylboron, dialkoxyboron or trialkyltin, and Y may be halogen or —O—SO₂CF₃.)

Two aromatic rings, or that is, a combination of a compound (I-6) and a compound (I-7), are reacted preferably in the presence of a transition metal catalyst and a suitable additive, thereby producing a biaryl compound (I-8). Typical methods for it are described in “Jikken Kagaku koza (Courses in Experimental Chemistry, 4th Ed)”, Vol. 25, Organic Synthesis VII, pp. 353-366, pp. 396-427, 1991 (Maruzen). The transition metal catalyst preferred for use herein includes various palladium complexes such as tetrakis(triphenylphosphine)palladium, and various nickel complexes such as dibromobis(triphenylphosphine)nickel. The additive also preferred for use herein includes triphenylphosphine, sodium carbonate, zinc; and these may be suitably selected depending on the method to which they are applied. In general, the reaction is conducted in a solvent at room temperature or with heating. Apart from the reaction described herein, also preferably used is a reaction for biaryl structure formation, for example, a reaction of a halogenated aryl compound with an aryl-Grignard reagent in the presence of a suitable transition metal catalyst.

(Production Methods for Starting Compounds)

The starting compounds to be used for producing the compounds of the present invention may be known compounds or may be produced by optionally processing known compounds according to the above-mentioned production methods, or according to methods well known to those skilled in the art (J. March, ADVANCED ORGANIC CHEMISTRY (John WILEY & SONS (1992)) (for example, acylation, alkylation, urea formation, oxidation, reduction (preferably, COMPREHENSIVE ORGANIC SYNTHESIS 8 REDUCTION (Pergamon Press) (1991)), halogenation).

Production Method (i):

Mitsunobu Reaction:

A starting compound (X) may be produced through Mitsunobu reaction of alcohols of general formulae (XI) and (XII). This reaction is conducted by stirring the compounds (XI) and (XII) in the presence of an equivalent or excessive amount of triphenylphosphine and diethyl azodicarboxylate, in an inert solvent as in the production method 1, under cooling to heating conditions.

(In the formula, the symbols have the following meanings: U represents an amino-protective group, ALK³ represents ALK¹ optionally substituted with HO, and the same shall be applied hereinunder.) Production Method (ii): Substitution Reaction:

This reaction is alkylation. A primary amine, a secondary amine, an alcohol, a thiol, a primary amide or a secondary amide is reacted with a reaction-corresponding amount of a compound having a leaving group, in a solvent inert to the reaction, in an equivalent ratio of the two, or in such a ratio that any one of the two is excessive, with stirring under cooling to heating conditions. As the case may be, the reaction may be conducted advantageously in the presence of a base (e.g., inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate; organic base such as TEA, diisopropylethylamine; metal alkoxide such as potassium tert-butoxide, sodium tert-butoxide; sodium hydride, lithium hydride) and an additive (tetra-n-butylammonium iodide, potassium iodide, sodium iodide) for smoothly promoting the reaction. The solvent inert to the reaction includes, for example, dichloromethane, DCE, chloroform, benzene, Tol, xylene, ether, THF, dioxane, EtOAc, ethanol, methanol, 2-propanol, acetonitrile, DMF, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylimidazolidinone, DMSO, acetone, methyl ethyl ketone, water, as well as their homogeneous or heterogeneous mixed solvents. The solvent may be suitably selected depending on various reaction conditions employed.

[In the formula, the symbols have the following meanings: Q represents O, S or NH, Z represents a leaving group (e.g., Cl, Br, I or OMs).] Production Method (iii):

This production method comprises reacting an aldehyde or ketone of a general formula (XVI) with a Wittig reagent or a Horner-Emmons reagent of a general formula (XVII), thereby producing a compound (XVI).

This reaction is conducted in the presence of an equivalent or excessive amount of a base (e.g., organic base such as TEA, diisopropylethylamine; inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate), by stirring the compound (XVI) and the compound (XVII) in the above-mentioned inert solvent, in an equivalent ratio of the two, or in such a ratio that any one of the two is excessive, under cooling to heating conditions. As the case may be, an additive (e.g., tetra-n-butylammonium iodide, potassium iodide) may be advantageously added to the system for smoothly promoting the reaction.

Z₁ represents a group used in a Wittig reagent or a Horner-Emmons reagent (e.g., phosphonium salt, or phosphorous diester),

n indicates 0 or 1.

[1] Screening Method of the Present Invention:

Fatty acid amide hydrolase (hereinafter this may be referred to as FAAH) includes enzymes having an activity of hydrolyzing anandamide, palmitoylethanolamide, oleamide, and/or 2-arachidonoyl glycerol, and so far as they are identified as those of the same molecule species, they may be derived from any species, for example, from mammals such as human (GenBank Accession Number NM_(—)001441), mouse (GenBank Accession Number NM_(—)010173), rat (GenBank Accession Number NM_(—)024132), porcine (GenBank Accession Number AB027132), rabbit, sheep, chicken, dog, cat, hamster, squirrel, bear, deer, monkey. In addition, it is not limited to a natural polypeptide, but may include artificially-produced mutants.

Regarding (a) a polypeptide which contains an amino acid sequence of the entire amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8 or a part of the amino acid sequence not having at least the transmembrane region-containing amino terminal region thereof, and which may hydrolyze anandamide, palmitoylethanolamide, oleamide, and/or 2-arachidonoyl glycerol;

(b) a polypeptide which contains an amino acid sequence of the entire amino acid sequence derived from the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8 through deletion, substitution and/or insertion of from 1 to 10, preferably from 1 to 7, more preferably from 1 to 5 amino acids therein, or a part of the amino acid sequence not having at least the transmembrane region-containing amino acid terminal region thereof, and which may hydrolyze anandamide, palmitoylethanolamide, oleamide, and/or 2-arachidonoyl glycerol;

(c) a polypeptide which contains an amino acid sequence having a homology of at least 70%, preferably at least 80%, more preferably at least 90%, most preferably at least 95% to the amino acid sequence represented by SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO:8, and which may hydrolyze anandamide, palmitoylethanolamide, oleamide, and/or 2-arachidonoyl glycerol;

(d) a polypeptide which contains an amino acid sequence of the entire amino acid sequence encoded by a polynucleotide represented by SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5 or SEQ ID NO:7 or by a polynucleotide capable of hybridizing with its complementary sequence under a stringent condition, or its part not having at least the transmembrane region-containing amino terminal region thereof, and which may hydrolyze anandamide, palmitoylethanolamide, oleamide, and/or 2-arachidonoyl glycerol;

the above (a) to (d) are generically referred to as a generic term “functional FAAH”.

The above-mentioned “transmembrane region-containing amino terminal region” as referred to in this description means an amino terminal region that includes the extracellular region at an amino terminal, and a transmembrane region buried in the cell membrane sandwiched between the extracellular region and the intracellular region. The existence and the site of the transmembrane region may be predicted from the amino acid sequence of the protein, using a protein membrane structure prediction program, TMpred, PSORT, SOSUI. Concretely, the “transmembrane region-containing amino terminal region” is, for example, the region of from the first to the 30th in SEQ ID NO:2, and the region of from the first to the 29th in SEQ ID NO:6. It is known that the polypeptide represented by the 30th to 579th amino acids in SEQ ID NO:6 excluding the region of from the 1st to the 29th in SEQ ID NO:6 also has the same enzymatic activity as that of the polypeptide from which the region is not excluded (Matthew et al., Biochemistry, Vol. 37, pp. 15177-15178, 1998).

The “homology” as referred to in this description means the values identities obtained by the use of the parameters prepared in default through search with Clustal V program (Higgins & Sharp, Gene, Vol. 73, pp. 237-244, 1998; Thompson et al., Nucleic Acid Res., Vol. 22, pp. 4673-7680, 1994). The parameters are as follows:

As pairwise alignment parameters,

-   -   K tuple 1     -   Gap Penalty 3     -   Window 5     -   Diagonals Saved 5.

The above-mentioned “stringent condition” for hybridization as referred to in this description means a condition not causing any unspecific binding. Concretely, for example, the hybridization is effected in a solution comprising 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate, pH 7), 5×Denhardt's solution (0.1% Ficoll 400, 0.1% polyvinylpyrrolidone, 0.1% BSA), modified salmon sperm DNA (50 g/ml), 0.1% SDS, and 10% dextran sulfate, under a temperature condition of from 37 to 42° C. for about 12 to 18 hours, and then optionally after pre-washed, this is washed with a washing solution (0.2×SSC, 0.1% SDS) under a temperature condition of from 50 to 60° C.

The above-mentioned “hydrolysis of anandamide, palmitoyl ethanolamide, oleamide and/or 2-arachidonoyl glycerol” as referred to in this description concretely means that, according to the method described in Examples 1 to 4, anandamide (N-arachidonoyl ethanolamine) is decomposed into arachidonic acid and ethanolamine; palmitoyl ethanolamide (N-palmitoyl ethanolamine) is into palmitic acid and ethanolamine; oleamide (cis-9,10-octadecenamide) is into oleic acid and ammonia, and 2-arachidonoyl glycerol is into arachidonic acid and glycerol, through hydrolysis in a buffer having a pH of from 7 to 9 at 4° C. to 37° C. for 30 minutes to 90 minutes.

The screening method of the present invention includes a screening method for a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain, comprising (1) a step of contacting a test substance with FAAH or functional FAAH, (2) a step of analyzing it for the activity of FAAH or functional FAAH, and (3) a step of selecting a substance that inhibits the activity of FAAH or functional FAAH.

(1) Step of Contacting Test Substance with FAAH or Functional FAAH:

For contacting a test substance with FAAH or functional FAAH, the test substance may be added to any of the following:

-   -   a) a cell or a tissue expressing FAAH or functional FAAH,     -   b) a transformant transformed with an expression vector         containing a polynucleotide that encodes FAAH or functional         FAAH,     -   c) a lysate or a homogenate of a) or b),     -   d) a purified product of FAAH or functional FAAH purified from         c), and incubated for a predetermined period of time; or     -   e) a tissue homogenate or blood of a test animal to which the         test substance has been administered may be used.         a) Cell or Tissue Expressing FAAH or Functional FAAH:

Concretely, the cell expressing FAAH or functional FAAH includes neurons, glial cells, epithelial cells, endothelial cells, lymphocytes, macrophages, platelets, mast cells, monocytes, dendritic cells, hepatocytes, renal cells, enterocytes, pancreatic cells, uterine cells, placental cells, bladder cells, prostatic cells, keratinization cells, and muscular cells. So far as they express FAAH or functional FAAH, these cells may be derived from any species; and for example, herein employable are cells derived from mammals such as human, mouse, rat, porcine, rabbit, sheep, chicken, dog, cat, hamster, squirrel, bear, deer, monkey.

For the cells, usable are established cell lines; and cells peeled from or isolated from animal tissues may also be used. The established cell lines usable herein include human bladder epithelial cancer-derived cell line 5673 cells, human prostatic cancer-derived cell line PC-3 cells, rat basophilic leukemia cell line RBL-2H3 cells, rat neuroblastoma cell line N18TG2 cells, rat glioma cell line C6 cells, rat macrophage cell line J774 cells, rat adrenal medulla-derived pheochromocytoma cell line PC-12 cells, human monocytic cell line U937 cells, human breast cancer cell line MFC-7 cells, human breast cancer cell line EFM-19 cells, human colon cancer-derived cell line CaCo-2 cells (these cell lines are available from American Type Culture Collection (ATCC)), human epidermal keratinocyte cell line HaCaT cells, and human neuroblastoma cell line CHP100 cells. Preferred are human bladder epithelial cancer-derived cell line 5673 cells, and rat basophilic leukemia cell line RBL-2H3 cells.

The tissue expressing FAAH or functional FAAH concretely includes brain, bladder, prostate, kidney, liver, testis, muscle, vessel, pancreas, digestive tube, lung, uterus, placenta, skin, lymphocyte, platelet, macrophage, monocyte, mast cell, and prostate. Preferably used are brain, liver and monocyte. So far as they express FAAH or functional FAAH, these tissues may be derived from any species. For example, tissues derived from mammals such as human, mouse, rat, porcine, rabbit, sheep, chicken, dog, cat, hamster, squirrel, bear, deer, monkey may be used.

For determining whether or not a cell or a tissue expresses FAAH or functional FAAH, a cell or tissue extract may be used and analyzed through western blotting, using an antibody capable of detecting the intended polypeptide, or through PCR (polymerase chain reaction) using primers capable of specifically detecting a polynucleotide that encodes the intended polypeptide. In addition, a lysate or a homogenate of a cell or a tissue is reacted with a substrate such as anandamide, palmitoyl ethanolamide, oleamide, and/or 2-arachidonoyl glycerol, in a buffer having a pH of from 7 to 9 at 4° C. to 37° C. for 30 minutes to 90 minutes, whereupon the system is determined whether or not the substrate is hydrolyzed for the intended determination.

b) Transformant Transformed with Expression Vector Containing Polynucleotide that Encodes FAAH or Functional FAAH:

A polynucleotide that encodes FAAH or functional FAAH may be isolated from a cDNA library through screening by PCR or hybridization, using primers and a probe planned and synthesized on the basis of the information of known amino acid sequences and base sequences.

The fragment that contains the isolated polynucleotide is inserted into a suitable expression vector, and it may be transfected into a host cell of eukaryote or prokaryote; and in the host cell, the polypeptide encoded by the transfected polynucleotide may be thus expressed. The expression vector may be any known one suitably selected depending on the host cell, for which, in addition, also usable is a vector plasmid suitably selected depending on the host cell and having a suitable promoter and a phenotype expression-related sequence introduced thereinto. Also usable is an expression vector with a specific sequence introduced thereinto in such a manner that the polypeptide encoded by the inserted polynucleotide may be expressed as fused with glutathion-S-transferase (GST) or with a tag such as Flag or His. In case where one cell is transformed with some different types of polynucleotides at the same time, then one expression vector to be used may be so planned that it includes such different types of polynucleotides, or those polynucleotides may be separately in different expression vectors. Alternatively, a cell with a chromosomal DNA having the constitution of the type may be produced and it may be used.

The expression vector with a desired polynucleotide introduced thereinto may be given to a host cell according to a DEAE-dextran method (Luthman et al., Nucleic Acids Res., Vol. 11, pp. 1295-1308, 1983), a calcium phosphate-DNA coprecipitation method (Graham et al., Virology, Vol. 52, pp. 456-457, 1973), a method of using a commercially-available transfection reagent, Lipofectamine 2000 (by Invitrogen) or FeGENE 6 (by Roche Molecular Biochemicals), or an electroporation method (Neumann et al., EMBO J., Vol. 1, pp. 841-845, 1982) for intended transformation. In case where E. coli is used as the host cell, a competent cell of E. coli is formed with coexistence with CaCl₂, MgCl₂ or RbCl according to a Hanahan's method (Hanahan et al., Mol. Biol. Vol. 166, pp. 557-580, 1983), and an expression vector with the desired polynucleotide introduced thereinto is given thereto for transformation of the cell.

c) Lysate or Homogenate of a) or b):

A cell homogenate may be prepared by washing a cell a few times with a buffer, and then homogenized using a Potter-Elvehjem homogenizer or the like thereby giving a uniform solution. A tissue homogenate may be prepared by adding a buffer cooled with ice to a tissue in an amount of from 5 to 10 volume times the weight of the tissue, homogenizing it using a Potter-Elvehjem homogenizer in ice thereby giving a uniform solution, and then further ultrasonically homogenizing it for a few seconds. The buffer may be Tris buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA) or Hepes buffer (1 mM EDTA, 100 mM NaCl, 12.5 mM Hepes, pH 8.0). For example, the test methods of Example 438 and Example 439 are applicable to the case. A lysate of E. coli transformed with an expression vector that contains an FAAH or functional FAAH-encoding polynucleotide may be prepared by collecting cells of E. coli through centrifugation and then dissolving them in a lysis buffer (for example, 20 mM Tris-HCl (pH 8.0), 500 mM NaCl, 10% glycerol, 0.2 mM EDTA, 0.5 mM DTT, 10 mM imidazole, 1% n-octyl-β-D-glucopyranoside).

d) Purified Product of FAAH or Functional FAAH Purified from c):

A purified product of FAAH or functional FAAH may be prepared from a) a cell or tissue expressing FAAH or functional FAAH or b) a lysate or a homogenate of a transformant transformed with an expression vector that contains an FAAH or functional FAAH-encoding polynucleotide, according to an ordinary purification method of affinity chromatography, electrochromatography, gel filtration chromatography, ion-exchange chromatography or partition chromatography.

Concretely, the purification is as follows: A cell or tissue expressing FAAH or functional FAAH is homogenized in a solvent containing sucrose, and then subjected to centrifugation and ultra-high-speed centrifugation to obtain a microsome fraction, thereafter this is dissolved in a solvent containing Triton-X and further centrifuged for deposit removal, and the resulting protein-lysate is processed in a high-performance protein liquid chromatography (FPLC) system (by Pharmacia) (Ueda et al., J. Biol. Chem., Vol. 270, pp. 23813-23827, 1995).

Alternatively, E. coli transformed so as to express a His tag-fused FAAH or functional FAAH is dissolved in a lysis buffer, then ultrasonically processed and centrifuged (e.g., at 10000×g for 20 minutes), and the resulting supernatant is mixed with a resin previously equilibrated with the lysis buffer and having a high affinity with His tag, at a low temperature for at least 12 hours. Then, the resin is washed, and the His tag-fused FAAH or functional FAAH is released from the resin to obtain its purified product.

For contacting a test substance with the above-mentioned cell or tissue, or the cell or tissue-lysate or homogenate prepared in the manner as above, or the purified FAAH or functional FAAH product, employable is a method of incubation for a predetermined period of time, with adding or not adding a test substance to them. Concretely, a test substance is dissolved in a solution suitably selected depending on its solubility therein, such as distilled water or dimethyl sulfoxide (DMSO), and is added to the above-mentioned cell or tissue, or the cell or tissue-lysate or homogenate, or the purified FAAH or functional FAAH product to be from 0.003 nM to 10 μM. The cell or tissue sample is incubated in a CO₂ incubator at 37° C. for 30 to 60 minutes; and the others are at 4° C. to 37° C. for 30 to 90 minutes, thereby attaining the intended contact with the test substance.

e) Tissue Homogenate or Blood of Test Animal Administered with Test Substance:

When a test substance is administered to a test animal, then the test substance may be contacted with the FAAH or functional FAAH existing in the tissue or the blood of the test animal. The test animal includes, for example, mammals such as mouse, rat, dog. A test substance may be administered to the test animal as follows: A test substance is suspended or dissolved in a carrier generally used in accordance with the property of the test substance, such as physiological saline water, dimethylformamide solution or 10% methyl cellulose solution, and it may be administered to a test animal orally, subcutaneously, intraperitoneally or intravenously. After the administration, the tissue is taken out, and the tissue is homogenized according to the method described in the above c), thereby preparing a tissue homogenate. Concretely, for example, from 1 to 3 mg/kg of a test substance is orally administered to a 9-week age rat, and its brain, liver or monocyte taken out of it after 30 minutes is homogenized to prepare the tissue homogenate Alternatively, from 0.3 to 3 mg/kg of a test substance is intravenously administered to a 13 to 18-month age dog, and its brain, liver or monocyte taken out of it after 30 minutes is homogenized to prepare the tissue homogenate. More concretely, for example, the tissue homogenate may be prepared according to the method described in Example 440. Blood may be collected from the heart or the descending aorta of a test animal to which the test substance has been administered.

(2) Step of Analyzing FAAH or Functional FAAH Activity Change:

For analyzing the FAAH or functional FAAH activity change, employable is a method of determining the change in the enzymatic activity of FAAH or functional FAAH based on the presence or absence of contact with a test substance. The enzymatic activity of FAAH or functional FAAH may be determined by contacting FAAH or functional FAAH with a substrate for a predetermined period of time, and measuring the amount of the decomposed product of the substrate. Alternatively, it may also be determined by measuring the amount of endocannabinoid that is an endogenous substrate for FAAH contained in a tissue or blood of a test animal.

For analyzing the test substance-dependent enzymatic activity change, a substrate is contacted with FAAH or functional FAAH for a predetermined period of time in the presence or absence of a test substance, and the ratio of the amount of the decomposed product of the substrate in the presence of the test substance to the amount of the decomposed product of the substrate in the absence of the test substance is obtained for the intended analysis.

Alternatively, FAAH or functional FAAH previously contacted with a test substance, and FAAH or functional FAAH not contacted with a test substance are separately contacted with a substrate for a predetermined period of time, and the ratio of the amount of the decomposed product of the substrate by the FAAH or functional FAAH previously contacted with the test substance to the amount of the decomposed product of the substrate by the FAAH or functional FAAH not contacted with the test substance is obtained whereby the test substance-dependent enzymatic activity change may be determined.

Further, the test substance-dependent enzymatic activity change may also be determined by measuring the amount of endocannabinoid in the tissue or blood of a test animal before and after administration of a test substance to the test animal, followed by obtaining the ratio of the endocannabinoid amount after the test substance administration to the endocannabinoid amount before the test substance administration; or by measuring the amount of endocannabinoid in the tissue or blood of a test animal administered or not administered with a test substance, followed by obtaining the ratio of the endocannabinoid amount in the tissue or blood of the test animal administered with the test substance to the endocannabinoid amount in the tissue or blood of the test animal not administered with the test substance, whereby the test substance-dependent enzymatic activity change may be determined.

FAAH and functional FAAH may be contacted with a substrate under the condition mentioned below, in accordance with the condition of the FAAH or functional FAAH.

For contacting the FAAH or functional FAAH expressed in the cell or tissue of a) or b) in the above (1) with a substrate, there may be employed a method of adding the substrate to the cultured cell or tissue in a buffer having a pH of from 7 to 9, and reacting them in a CO₂ incubator at 37° C. or room temperature preferably for 30 to 60 minutes. The reaction may be stopped by transferring the cell or tissue onto ice to rapidly cool it, whereupon an FAAH inhibitor may be contacted with it at its sufficient concentration; or by adding a 1:1 (by volume) solution of chloroform and methanol thereto. The cell or tissue is lysed or homogenized according to the method described in the above (1)c), thereby producing a lysate or a homogenate thereof.

For contacting FAAH or functional FAAH in the lysate or homogenate of a cell or tissue in c) or e) in the above (1), with a substrate, there may be employed a method of adding the substrate to the lysate or homogenate that has been diluted with a buffer having a pH of from 7 to 9 so as to have a protein concentration of preferably from 10 to 100 μg/ml, and reacting them under a temperature condition of from 4° C. to 37° C. The reaction time may be suitably defined depending on the condition such as the amount of the enzyme added, the amount of the substrate added and the reaction temperature. For example, when they are reacted at room temperature, the reaction time may be from 30 to 90 minutes.

For contacting the purified FAAH or functional FAAH in the above (1) d) with a substrate, there may be employed a method of adding the substrate to a lysate or a homogenate that has been diluted with a buffer having a pH of from 7 to 9, and reacting them under a temperature condition of from 4° C. to 37° C. The reaction time may be suitably defined depending on the condition such as the amount of the enzyme added, the amount of the substrate added and the reaction temperature. For example, when they are reacted at room temperature, the reaction time may be from 30 to 90 minutes.

For measuring the amount of the decomposed product of a substrate, the unreacted substrate and the decomposed product in the enzyme reaction solution are separated from each other, and the amount of the decomposed product may be measured. For separating the unreacted substrate from the decomposed product, the water-solubility of the decomposed product, ethanolamine may be utilized. For example, a 1:1 (by volume) solution of chloroform and methanol is added to the enzyme reaction solution in an amount of 2 times the reaction solution, followed by stirring, and then centrifuged, whereby the decomposed product containing in the upper layer, water/ethanol layer may be separated from the unreacted substrate contained in the lower layer, chloroform layer. Alternatively, the system may be mixed with a liquid scintillation cocktail agent of no water absorbability whereby the fat-soluble unreacted radioactive substrate may be taken into the cocktail agent and the decomposed product may be thereby separated from the unreacted substrate. Still alternatively, the unreacted substrate may be separated from the decomposed product through thin-layer chromatography or high-performance liquid chromatography.

In case where a ³H- or ¹⁴C-labeled substrate, or a mixture of a labeled substrate and an unlabeled substrate is used, the amount of the decomposed product or the amount of the unreacted substrate may be measured with a liquid scintillation counter, or it may be recorded as an X-ray latent image on an imaging plate and may be measured with an image plate reader.

In case where an unlabeled substrate is used, the absorbance at 205 nm of the system may be monitored through high-performance liquid chromatography, and the amount of the decomposed product or the amount of the unreacted substrate may be thereby measured (Lang et al., Anal. Biochem., Vol. 238, pp. 40-45, 1996).

When the amount of the unreacted substrate is measured, then amount of the unreacted substrate may be subtracted from the amount of the substrate added before the reaction, and the amount of the decomposed product may be thereby obtained. Alternatively, the amount of the decomposed product of the substrate measured in a buffer alone not containing FAAH or functional FAAH, as a control, may be subtracted from the amount of the decomposed product of the substrate with FAAH or functional FAAH, whereby the net amount of the decomposed product of the substrate with FAAH or functional FAAH may be obtained.

The amount of endocannabinoid in a tissue homogenate may be measured, for example, by homogenizing a sample tissue with a 2:1:1 (by volume) solution of chloroform, methanol and 50 mM Tris (pH 8.0), followed by measuring the amount of the endocannabinoid contained in the organic layer (chloroform layer) through liquid chromatography/isotope dilution mass spectrometry (Cravatt et al., Proc., Natl. Acad. Sci. USA, Vol. 98, pp. 9371-9376, 2001).

The amount of endocannabinoid in blood may be measured, for example, as follows: Plasma is separated from a blood sample, and the protein in the plasma is removed through centrifugation along with the same amount of acetone (−20° C.) added thereto. Acetone is evaporated by a nitrogen jet applied to the system, and a 1:2 (by volume) solution of methanol and chloroform is added to it, and the amount of endocannabinoid contained in the organic layer (chloroform layer) is measured through liquid chromatography/isotope dilution mass spectrometry (Giuffraida et al., Eur. J. Pharmacol., Vol. 408, pp. 161-168, 2000).

(3) Step of Selecting Substance that Inhibits the Activity of FAAH or Functional FAAH:

A substance that inhibits the activity of FAAH or functional FAAH may be selected as follows: A test substance is contacted with FAAH or functional FAAH, this is compared with a case not contacted with the test substance, and a substance that decreases the amount of the decomposed product of the substrate may be selected.

Concretely, a test substance is contacted with FAAH or functional FAAH, and this is compared with a case not contacted with a test substance. In this, the substance with which the amount of the decomposed product of the enzyme decreases preferably to ½ or less may be screened for a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain.

Alternatively, a test substance having a different concentration is contacted with FAAH or functional FAAH; and based on the amount of the decomposed product of the substrate not contacted with the test substance, as 100%, the relative value (%) of the decomposed product of the substrate contacted with the test substance having a different concentration is obtained; or based on the amount of the decomposed product of the substrate not contacted with the test substance, as 100%, and based on the amount of the decomposed product of the substrate in a case where a known FAAH inhibitor having a sufficient concentration is contacted with FAAH or functional FAAH for a sufficient period of time, as 0%, the relative value (%) of the amount of the decomposed product of the substrate contacted with the test substance having a different concentration is obtained. In an inhibition curve drawn on a graph in which the relative value (%) of the decomposed product of the substrate is on the vertical axis and the concentration of the test substance is on the horizontal axis, the concentration of the test substance that gives a relative value, 50%, of the decomposed product of the substrate (IC₅₀ value) is computed; and the substance of which the IC₅₀ value is preferably at most 1 μM, more preferably at most 100 nM is screened for a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain. For example, the tests of Example 438 to Example 440 are referred to.

Still alternatively, a test substance is administered to a test animal, and the amount of endocannabinoid in the tissue or blood of the animal is compared with each other before and after the test substance administration; and the substance that increases the amount preferably to 1.5 times may be selected for a substance that inhibits the activity of FAAH or functional FAAH, or that is, the substance may be screened for a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain.

[2] Test Substance:

Not specifically defined, the test substance for use in the screening method of the present invention includes, for example, commercially-available products (including peptides), various known compound registered in Chemical File (including peptides), compound groups obtained according to combinatorial chemistry technology (Terrett et al., J. Steele. Tetrahedron, Vol. 51, pp. 8135-8173, 1995), microorganisms-derived culture supernatants, plant or sea life-derived natural components, animal tissue extracts, as well as compounds (including peptides) produced through chemical or biological modification of the compounds (including peptides) selected according to the screening method of the present invention.

[3] Pharmaceutical Composition for Treatment of Urinary Frequency and Urinary Incontinence, for Treatment of Overactive Bladder and/or for Treatment of Pain:

As the active ingredient of the pharmaceutical composition of the present invention, usable is a substance that inhibits the activity of FAAH or functional FAAH, in which the inhibitor substance may be selected, for example, according to the screening method of the present invention.

The pharmaceutical composition of the present invention is not limited to a pharmaceutical composition that contains, as the active ingredient thereof, the substance obtained according to the screening method of the present invention, but may include any and every pharmaceutical composition for treatment of urinary frequency and urinary incontinence, for treatment of overactive bladder and/or for treatment of pain that contains, as the active ingredient thereof, a substance to inhibit the activity of FAAH or functional FAAH; and preferably, this is a pharmaceutical composition for treatment of urinary frequency and urinary incontinence, for treatment of overactive bladder and/or for treatment of pain.

The effect for treatment of urinary frequency and urinary incontinence, the effect for treatment of overactive bladder and/or the effect for treatment of pain may be confirmed in the manner as above.

The composition containing, as the active ingredient thereof, a substance that inhibits the activity of FAAH or functional FAAH, for example, DNA, protein (including antibody or antibody fragment), peptide or any other compound may be prepared as a pharmaceutical composition using pharmaceutically acceptable carrier, excipient and/or any other additive generally used in preparation of pharmaceutical compositions, depending on the type of the active ingredient therein.

The administration of the composition can be accompanied by, for example, oral administration via tablets, pills, capsules, granules, fine granules, powders or oral liquids; or parenteral administration via injections such as intravenous, intramuscular or intraarticular injections, suppositories, endermic preparations or intramucosal preparations. Especially for peptides that are digested in stomach, parenteral administration such as intravenous injection is preferred.

The solid composition for oral administration may comprise a mixture of at least one or more active ingredients and at least one inert diluents, for example, lactose, mannitol, glucose, microcrystalline cellulose, hydroxypropyl cellulose, starch, polyvinylpyrrolidone or magnesium aluminometasilicate. In addition to inert diluents, the solid composition may contain other additives, in an ordinary manner, for example, lubricants, disintegrators, stabilizers, solubilizers or solubilization assisting agents. The tablets and pills may be optionally coated with sugar or with gastric or enteric coat film.

The liquid composition for oral administration includes, for example, emulsions, solutions, suspensions, syrups and elixirs, and may contain ordinary inert diluents, for example, purified water or ethanol. In addition to inert diluents, the liquid composition may also contain, for example, moistening agents, suspending agents, sweeteners, aromatics or antiseptics.

Injections for parenteral administration includes aseptic aqueous or non-aqueous solutions, suspensions or emulsions. The aqueous solutions or suspensions may contain, for example, distilled water for injection or physiological saline, as a diluent. The diluents for the non-aqueous solutions or suspensions includes, for example, propylene glycol, polyethylene glycol, vegetable oil (e.g., olive oil), alcohols (e.g., ethanol) or Polysorbate 80. Such compositions may further contain moistening agents, emulsifiers, dispersants, stabilizers, solubilizers or solubilization assisting agents, or antiseptics. Such compositions may be sterilized, for example, by filtration through a bacteria retaining filter, or through addition of a germicide thereto, or through irradiation. If desired, a germ-free solid composition may be prepared, and before use, it may be dissolved in germ-free water or in any other germ-free medium for injection.

The dose of the composition may be suitably determined depending on the intensity of the activity of the active ingredient, or that is, the substance obtained according to the screening method of the present invention, and on the symptom, the age and the sex of the subject for its administration.

For example, in oral administration, the dose may be generally from about 0.1 to 100 mg/day, preferably from 0.1 to 50 mg/day to an adult (body weight of 60 kg). In parenteral administration, the injection dose may be from 0.01 to 50 mg/day, preferably from 0.01 to 10 mg/day.

EXAMPLES

The present invention is described in more detail with reference to the following Examples. The compounds of the present invention should not be limited to the compounds described in the following Examples. Production methods of starting compounds are shown in Reference Examples. Some compounds of the present invention may also be starting compounds for others; and for convenience sake, their production methods may be given herein as Reference Examples. The chemical structural formulae and the physicochemical properties of the compounds obtained in Reference Examples are shown in Tables 1 to 15. The chemical structural formulae of the compounds obtained in Examples are shown in Table 16 to Table 34; and the physicochemical properties thereof are in Tables 35 to 63. The structures of other compounds of the present invention are shown in Tables 65 to 73. These compounds may be readily produced according to the above-mentioned production methods or the methods described in the following Reference Examples and Examples, or according to methods self-obvious to those skilled in the art, or according to modifications of those methods.

When commercially-available kits are used, the written instructions attached thereto may be referred to.

The abbreviations given in this descriptions are as follows:

-   -   Rex: Reference Example     -   Ex: Example     -   Str: structural formula     -   DAT: physicochemical properties

¹H-NMR δ(ppm), solvent: nuclear magnetic resonance spectrum

In the physicochemical data of the compounds of Examples;

-   -   DMSO: DMSO-d6     -   MS m/z: mass spectral data     -   Com: compound     -   NC: cyano     -   Ph: phenyl     -   Me: methyl     -   diMe: dimethyl     -   Et: ethyl     -   Pr: propyl     -   iPr: isopropyl     -   Bu: butyl     -   tBu: tert-butyl     -   iBu: isobutyl     -   Pen: pentyl     -   Hex: hexyl     -   Hep: heptyl     -   Oct: octyl     -   cPr: cyclopropyl     -   cPen: cyclopentyl     -   cHex: cyclohexyl     -   cHep: cycloheptyl     -   cOct: cyclooctyl     -   Ac: acetyl     -   Cl: chloro     -   diCl: dichloro     -   CN: cyano     -   F: fluoro     -   diF: difluoro     -   FPh fluorophenyl     -   NCPh: cyanophenyl     -   diFPh: difluorophenyl     -   O₂N: nitro     -   MeO: methoxy     -   diMeO: dimethoxy     -   Br: bromo     -   diBr: dibromo     -   BrPh: bromophenyl     -   F₃C: trifluoromethyl     -   AcO: acetoxy     -   MeOCO or COOMe: methoxycarbonyl     -   tBuOCO or COOtBu: tert-butoxycarbonyl     -   HO: hydroxy     -   HOPh: hydroxyphenyl     -   H₂N: amino     -   PhCONH: benzoylamino     -   EtCONH: ethylcarbonylamino     -   Me₂N: dimethylamino     -   Et₂N: diethylamino     -   BIP2: 2-biphenyl     -   BIP3: 3-biphenyl     -   BIP4: 4-biphenyl     -   BIP5: 5-biphenyl     -   BIP6: 6-biphenyl     -   Thiop2: thiophen-2-yl     -   Thiop3: thiophen-3-yl     -   Thiop4: thiophen-4-yl     -   Thiop5: thiophen-5-yl     -   PYRR1: pyrrolidin-1-yl     -   PYRR2: pyrrolidin-2-yl     -   PYRR3: pyrrolidin-3-yl     -   PYRR4: pyrrolidin-4-yl     -   PYRR5: pyrrolidin-5-yl     -   Py2: pyridin-2-yl     -   Py3: pyridin-3-yl     -   Py4: pyridin-4yl     -   Py5: pyridin-5-yl     -   IM1: imidazol-1-yl     -   IM2: imidazol-2-yl     -   IM3: imidazol-3-yl     -   IM4: imidazol-4-yl     -   BenzIM1: benzimidazol-1-yl     -   BenzIM2: benzimidazol-2-yl     -   BenzIM3: benzimidazol-3-yl     -   BenzIM4: benzimidazol-4-yl

BenzIM5: benzimidazol-5-yl

BenzIM6: benzimidazol-6-yl

-   -   Pyrazi1: pyrazin-1-yl     -   Pyrazi2: pyrazin-2-yl     -   Pyrazi3: pyrazin-3-yl     -   Pyrazi4: pyrazin-4-yl     -   Pyrazi5: pyrazin-5-yl     -   Pyrazi6: pyrazin-6-yl     -   PIPE1: piperidin-1-yl     -   PIPE2: piperidin-2-yl     -   PIPE3: piperidin-3-yl     -   PIPE4: piperidin-4-yl     -   PIPE5: piperidin-5-yl     -   PIPE6: piperidin-6-yl     -   PIPERA: piperazine     -   PIPERA1: piperazin-1-yl     -   PIPERA2: piperazin-2-yl     -   PIPERA3: piperazin-3-yl     -   PIPERA4: piperazin-4-yl     -   PIPERA5: piperazin-5-yl     -   Pyrazo1: pyrazol-1-yl     -   Pyrazo2: pyrazol-2-yl     -   Pyrazo3: pyrazol-3-yl     -   Pyrazo4: pyrazol-4-yl     -   Pyrazo5: pyrazol-5-yl     -   Mo: morpholine     -   Mo2: morpholin-2-yl     -   Mo3: morpholin-3-yl     -   Mo4: morpholin-4-yl     -   Mo5: morpholin-5-yl     -   Azep: hexahydroazepine     -   Azep1: hexahydroazepin-1-yl     -   Azep2: hexyhydroazepin-2-yl     -   Azep3: hexyhydroazepin-3-yl     -   Azep4: hexyhydroazepin-4-yl     -   Thiaz2: thiazol-2-yl     -   Thiaz3: thiazol-3-yl     -   Thiaz4: thiazol-4-yl     -   Thiaz5: thiazol-5-yl     -   QUI1: quinolin-1-yl     -   QUI2: quinolin-2-yl     -   QUI3: quinolin-3-yl     -   QUI4: quinolin-4-yl     -   QUI5: quinolin-5-yl     -   QUI6: quinolin-6-yl     -   QUI7: quinolin-7-yl     -   QUI8: quinolin-8-yl     -   ISOQUI2: isoquinolin-2-yl     -   ISOQUI3: isoquinolin-3-yl     -   ISOQUI4: isoquinolin-4-yl     -   ISOQUI5: isoquinolin-5-yl     -   ISOQUI6: isoquinolin-6-yl     -   ISOQUI7: isoquinolin-7-yl     -   ISOQUI8: isoquinolin-8-yl     -   NAPH1: naphthalen-1-yl     -   NAPH2: naphthalen-2-yl     -   NAPH3: naphthalen-3-yl     -   NAPH4: naphthalen-4-yl     -   NAPH5: naphthalen-5-yl     -   TEA: triethylamine     -   Sal: addition salt     -   HCl: hydrochloride     -   oxal: oxalate     -   fum: fumarate     -   p-tol: p-toluenesulfonate

Reference Example 1

A THF (10 ml) solution containing phenol (471 mg) and diethyl azodicarboxylate (2.83 g, 40% Tol solution) was dropwise added to a THF (15 ml) solution containing tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.57 g) and triphenylphosphine (1.70 g), at 0° C., followed by stirring at room temperature for 24 hours. Water (40 ml) was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with an aqueous 1 M sodium hydroxide solution and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane:EtOAc=4:1 (v/v)) to obtain a colorless oil (1.14 g). The resulting compound was dissolved in EtOAc, a 4 M hydrogen chloride/EtOAc solution (9.6 ml) was added thereto, followed by stirring at room temperature for 5 hours to obtain 4-(phenoxymethyl)piperidine hydrochloride (680 mg) as colorless powder.

In the same manner as in Reference Example 1, the compounds of Reference Examples 2 to 27 were obtained.

Reference Example 28

Water (10 ml), sodium carbonate (4.76 g) and tetrakistriphenylphosphine palladium (866 mg) were added in that order to a dimethoxyethane (50 ml) solution containing 3-bromobenzamide (3.0 g) and (3-hydroxyphenyl)boronic acid (2.27 g), followed by stirring at 60° C. for 24 hours. The reaction solution was cooled, diluted with EtOAc, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: EtOAc) to obtain a pale yellow powder (2.74 g). Using the resulting compound and in the same manner as in Reference Example 1, the compound of Reference Example 28 was obtained.

Reference Example 29

A THF (80 ml) solution containing 4-(benzyloxy)phenol (8.0 g) and diethyl azodicarboxylate (26 ml, 40% Tol solution) was dropwise added to a THF (80 ml) solution containing tert-butyl 4-hydroxypiperidine-1-carboxylate (12 g) and triphenylphosphine (16 g) at 0° C., followed by stirring at room temperature for 24 hours. Water (40 ml) was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with an aqueous 1 M sodium hydroxide solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=8:1 (v/v)) to obtain a colorless oil (12.4 g).

10% palladium-carbon (catalytic amount) was added to an ethanol (100 ml) solution containing the resulting compound (5.18 g), followed by stirring in a hydrogen gas atmosphere at room temperature under normal pressure for 16 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to obtain a pale brown solid (4.0 g).

1-(Bromomethyl)-3-fluorobenzene (2.5 ml) and potassium carbonate (2.8 g) were added to an acetonitrile (100 ml) solution containing the resulting compound (4.0 g), followed by heating at 80° C. for 22 hours. The solid matter was removed by filtration, the resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=8:1 (v/v)) to obtain a colorless solid (5.15 g).

The resulting compound (5.15 g) was dissolved in EtOAc (20 ml), a 4 M hydrogen chloride/EtOAc solution (20 ml) was added thereto, followed by stirring at room temperature for 5 hours. Then, the solvent was evaporated under reduced pressure. The residue was dissolved in water, neutralized with an aqueous 1 M sodium hydroxide solution, and the solid formed was dried to obtain 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine (3.70 g).

In the same manner as in Reference Example 29, the compounds of Reference Examples 30 to 36 were obtained.

Reference Example 37

Diethyl azodicarboxylate (11 ml, 40% Tol solution) was dropwise added to a THF (30 ml) solution containing tert-butyl 4-hydroxypiperidine-1-carboxylate (4.6 g), triphenylphosphine (6.1 g) and 6-chloro-2-pyridinol (2.0 g) at 0° C., followed by stirring at room temperature for 24 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with an aqueous 1 M sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl 4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (3.8 g).

(3-Fluorophenyl)methanol (220 mg) and potassium tert-butoxide (200 mg) were added to a DMF (5 ml) solution containing tert-butyl 4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (500 mg), followed by heating at 100° C. for 30 minutes. Then, (3-fluorophenyl)methanol (220 mg) and potassium tert-butoxide (200 mg) were added thereto, followed by heating at 110° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain a white solid (420 mg).

The resulting compound (400 mg) was dissolved in EtOAc (5 ml), a 4 M hydrogen chloride/EtOAc solution (3 ml) was added thereto, followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc, and dried under reduced pressure to obtain 2-[(3-fluorobenzyl)oxy]-6-(4-piperidinoxy)pyridine hydrochloride (310 mg).

In the same manner as in Reference Example 37, the compound of Reference Example 38 was obtained.

Reference Example 39

Water (4 ml), sodium carbonate (610 mg) and tetrakistriphenylphosphine palladium (110 mg) were added in that order to a Tol (10 ml) solution containing tert-butyl 4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (500 mg) and [3-(aminocarbonyl)phenyl]boronic acid (320 mg), followed by heating overnight at 100° C. The reaction solution was cooled and diluted with EtOAc. The organic layer was washed with an aqueous solution of anhydrous sodium hydrogencarbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:2 (v/v)) to obtain a pale yellow powder (590 mg).

The resulting compound (590 mg) was dissolved in EtOAc (5 ml), and a 4 M hydrogen chloride/EtOAc solution (5 ml) was added thereto, followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc, and dried under reduced pressure to obtain 3-[6-(4-piperidinyloxy)-2-pyridinyl]benzamide hydrochloride (440 mg).

Reference Example 40

TEA (4.6 ml) and methanesulfonyl chloride (2.0 ml) were dropwise added to a methylene chloride (80 ml) solution containing tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (5.0 g) at 0° C., followed by stirring at room temperature for 3 hours. An aqueous sodium hydrogencarbonate solution and methanol were added to the reaction solution, followed by stirring at room temperature for 30 minutes. This was extracted with chloroform, and the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain a colorless solid (6.1 g).

Sodium hydride (541 mg, 60% in oil) was added to a DMF (80 ml) solution containing the resulting compound (2.0 g) and phenylpropanol (1.3 g) at 0° C., followed by heating at 100° C. for 20 hours. The reaction solution was cooled, water was added thereto, followed by extraction with EtOAc. This was washed with an aqueous 1 M hydrochloric acid solution, an aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1 (v/v)) to obtain a yellow oil (1.96 g).

The resulting compound (1.96 g) was dissolved in EtOAc (5 ml), and a 4 M hydrogen chloride/EtOAc solution (10 ml) was added thereto, followed by stirring at room temperature for 2 hours. The solid formed was collected by filtration and dried to obtain 4-[2-(3-phenylpropoxy)ethyl]piperidine hydrochloride (1.55 g).

Reference Example 41

TEA (2.30 ml) and methanesulfonyl chloride (1.22 ml) were dropwise added to a THF (40 ml) solution containing tert-butyl 4-hydroxypiperidine-1-carboxylate (3.02 g) at 0° C., followed by stirring at room temperature for 1 hour. EtOAc (50 ml) and water (50 ml) were added to the reaction solution. The organic layer was washed with aqueous 5% citric acid solution, an aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a pale orange oil. The resulting oil was dissolved in DMA (25 ml), and cesium carbonate (5.38 g) and 4-sulfanylphenol (1.89 g) were added thereto, followed by heating at 50° C. for 2 hours. The reaction solution was cooled, water was added thereto, followed by extraction with EtOAc. The organic layer was washed with an aqueous 1 M hydrochloric acid solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=4:1 (v/v)) to obtain tert-butyl 4-[(4-hydroxyphenyl)sulfanyl]piperidine-1-carboxylate (3.40 g) as colorless powder.

1-(Bromomethyl)-3-fluorobenzene (0.436 ml) and potassium carbonate (670 mg) were added to an acetonitrile (15 ml) solution containing tert-butyl 4-[(4-hydroxyphenyl)sulfanyl]piperidine-1-carboxylate (1.00 g), followed by heating at 80° C. for 2 hours. The reaction solution was cooled, saturated brine was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=8:1 (v/v)) to obtain tert-butyl 4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine-1-carboxylate (1.50 g) as colorless powder.

Tert-butyl 4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine-1-carboxylate (501 mg) was dissolved in EtOAc (5 ml), and a 4 M hydrogen chloride/EtOAc solution (3 ml) was added thereto, followed by stirring at room temperature for 3 hours. Then, the solvent was evaporated under reduced pressure. The residue was dissolved in water, neutralized with an aqueous 1 M sodium hydroxide solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine (328 mg).

In the same manner as in Reference Example 41, the compound of Reference Example 42 was obtained.

Reference Example 43

mCPBA (1.64 g) was added to a chloroform (20 ml) solution containing tert-butyl 4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfanyl)piperidine-1-carboxylate (1.50 g) obtained in the method of Reference Example 41, at 0° C., followed by stirring at room temperature for 17 hours. The solid was removed by filtration, and an aqueous 10% sodium sulfate solution was added to the filtrate, followed by extraction with chloroform. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=2:1 (v/v)) to obtain a colorless powder (1.58 g). The resulting powder (1.56 g) was dissolved in EtOAc (10 ml), a 4 M hydrogen chloride/EtOAc solution (8 ml) was added thereto, followed by stirring at room temperature for 2 hours. Then, the solid was collected by filtration and washed with EtOAc to obtain 4-({4-[(3-fluorobenzyl)oxy]phenyl}sulfonyl)piperidine hydrochloride (1.13 g) as colorless powder.

In the same manner as in Reference Example 43, the compounds of Reference Examples 44 to 46 were obtained.

Reference Example 47

A THF (5 ml) solution of tert-butyl 4-[(4-hydroxyphenyl)sulfanyl]piperidine-1-carboxylate (495 mg) obtained in the method of Reference Example 41 and diethyl azodicarboxylate (1.04 g, 40% Tol solution) were dropwise added to a THF (5 ml) solution containing cyclohexylmethanol and triphenylphosphine (629 mg), at 0° C., followed by stirring at room temperature for 24 hours. Water (40 ml) was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with an aqueous 1 M sodium hydroxide solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=9:1 (v/v)) to obtain tert-butyl 4-{[4-(cyclohexylmethoxy)phenyl]sulfonyl}piperidine-1-carboxylate (744 mg) as pale yellow oil.

The resulting tert-butyl 4-{[4-(cyclohexylmethoxy)phenyl]sulfonyl}piperidine-1-carboxylate (635 mg) was dissolved in EtOAc (7 ml), and a 4 M hydrogen chloride/EtOAc solution (3.6 ml) was added thereto, followed by stirring at room temperature for 6 hours. The solid was collected by filtration and washed with EtOAc to obtain 4-{[4-(cyclohexylmethoxy)phenyl]sulfonyl}piperidine hydrochloride (485 mg) as colorless powder.

In the same manner as in Reference Example 47, the compound of Reference Example 48 was obtained.

Reference Example 49

Sodium hydride (355 mg, 60% in oil) and benzyl bromide (1.0 ml) were added to a THF (40 ml) solution containing tert-butyl 4-hydroxypiperidine-1-carboxylate (1.5 g), followed by heating at 60° C. for 13 hours. The reaction solution was cooled, water was added thereto, followed by extraction with EtOAc. This was washed with an aqueous 1 M hydrochloric acid solution, an aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain a colorless oil (1.91 g).

The resulting compound (1.8 g) was dissolved in EtOAc (5 ml), and a 4 M hydrogen chloride/EtOAc solution (15 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was diluted with isopropyl ether, and the solid formed was collected by filtration and dried to obtain 4-(benzyloxy)piperidine hydrochloride (1.32 g).

In the same manner as in Reference Example 49, the compounds of Reference Examples 50 to 53 were obtained.

Reference Example 54

Diethyl azodicarboxylate (2.6 ml, 40% Tol solution) was dropwise added to a THF (10 ml) solution containing (3-fluorophenyl)methanol (730 mg), triphenylphosphine (1.5 g) and 6-chloro-3-pyridinol (500 mg) at 0° C., followed by stirring at room temperature for 24 hours. The reaction solution was diluted with EtOAc. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=8:1 (v/v)) to obtain a white solid (810 mg).

Tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g) and potassium tert-butoxide (570 mg) were added to a DMF (10 ml) solution containing the resulting white solid (800 mg), followed by heating at 130° C. for 1 hour. Then, potassium tert-butoxide (400 mg) was added thereto, followed by further heating at 130° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with EtOAc, washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=7:1 (v/v)) to obtain a white solid (350 mg).

The resulting compound (345 mg) was dissolved in EtOAc (3 ml), and a 4 M hydrogen chloride/EtOAc solution (2 ml) was added thereto, followed by stirring overnight at room temperature. The solid precipitated was collected by filtration, washed with EtOAc, and dried under reduced pressure to obtain 6-[(3-fluorobenzyl)oxy]-2-(4-piperidinoxy)pyridine hydrochloride (260 mg).

Reference Example 55

[1-(Tert-butoxycarbonyl)piperidin-4-yl]acetic acid (0.60 g) was dissolved in dimethylformamide (12 ml), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.89 g), 1-hydroxybenzotriazole (0.50 g) and benzylamine (0.40 g) were added thereto, followed by stirring at room temperature for 15 hours. Water was added to the reaction solution and stirred for 1 hour. Then, sodium hydrogencarbonate solution was added thereto, followed by extraction with EtOAc. The organic layer was washed with 0.5 M hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:2 (v/v)) to obtain a colorless powder (0.69 g).

The resulting compound (0.69 g) was dissolved in EtOAc (10 ml), and a 4 M hydrogen chloride/EtOAc solution (2.2 ml) was added thereto, followed by stirring at room temperature for 20 hours. The reaction solution was concentrated into a dry solid to obtain N-benzyl-2-piperidin-4-ylacetamide hydrochloride (0.62 g).

Reference Example 56

Phosphoric acid (7 ml) and diphosphorus pentoxide (14 g) were heated at 150° C. for 30 minutes, N-methylbenzene-1,2-diamine (1.3 g) and 4-piperidin-4-ylbutanoic acid hydrochloride (1.5 g) were added thereto, followed by heating at 120° C. for 3 hours. The reaction solution was poured into water, neutralized with aqueous sodium hydroxide solution, and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol:aqueous ammonia=10:1:0.1 (v/v/v)) to obtain 1-methyl-2-(3-piperidin-4-ylpropyl)-1H-benzimidazole (1.61 g).

Reference Example 57 and Reference Example 58

Potassium tert-butoxide (1.72 g) was added to a THF (30 ml) solution containing [4-(methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (7.51 g) at 0° C., followed by stirring for 1 hour. A THF (20 ml) solution containing tert-butyl 4-formylpiperidine-1-carboxylate (Beilstein Registry No. 7704210, 2.96 g) was dropwise added to the reaction solution at 0° C., followed by stirring for 14 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc 9:1 (v/v)) to obtain a yellow oil (3.77 g).

The resulting compound (3.75 g) was dissolved in methanol (20 ml) and THF (10 ml), and an aqueous 1 M sodium hydroxide solution (16.3 ml) was added thereto, followed by stirring at 50° C. for 4 hours. The reaction solution was cooled, and the solvent was evaporated under reduced pressure. This was made acidic with 1 M hydrochloric acid added, and the solid precipitated was collected by filtration and washed with water to obtain a pale brown powder (2.82 g).

Ammonium chloride (2.26 g), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (3.24 g), 1-hydroxybenzotriazole (1.14 g) and TEA (5.88 ml) were added to a DMF (30 ml) solution containing the resulting compound (2.80 g), followed by stirring at room temperature for 32 hours. Water was added to the reaction solution, and the solid precipitated was collected by filtration and washed with water to obtain a pale brown powder (2.61 g).

The resulting compound (2.58 g) was dissolved in EtOAc (15 ml), and a 4 M hydrogen chloride/EtOAc solution (15 ml) was added thereto, followed by stirring at room temperature for 8 hours. The solid formed was collected by filtration, washed with EtOAc, and dried to obtain 4-[(E)-2-piperidin-4-ylvinyl]benzamide hydrochloride (1.92 g) (Reference Example 57).

10% Palladium-carbon (catalytic amount) was added to a methanol (15 ml)/water (5 ml) solution containing 4-[(E)-2-piperidin-4-ylvinyl]benzamide hydrochloride (800 mg), followed by stirring in a hydrogen gas atmosphere at room temperature under normal pressure for 4 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting solid was recrystallized from ethanol/acetonitrile to obtain 4-(2-piperidin-4-ylethyl)benzamide hydrochloride (451 mg) (Reference Example 58).

Reference Example 59

Sodium triacetoxyborohydride (2.2 g) was added to a dichloromethane (30 ml) solution containing tert-butyl 4-(4-aminophenoxy)-1-piperidinecarboxylate (2.0 g, Beilstein Registry No. 9262581), cyclohexenecarbaldehyde (770 mg) and acetic acid (1.25 g), at 0° C., followed by stirring at room temperature for 2 hours. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from EtOAc/hexane to obtain a pale brown crystal (2.0 g).

Sodium triacetoxyborohydride (1.1 g) was added to a dichloromethane (20 ml) solution containing the resulting crystal (970 mg), an aqueous 37% formaldehyde solution (0.94 ml) and acetic acid (0.75 g), at 0° C., followed by stirring at room temperature for 2 hours. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting oil was dissolved in EtOAc (15 ml). A 4 M hydrogen chloride/EtOAc solution (5 ml) was added thereto, followed by stirring overnight at room temperature. The solid precipitated was collected by filtration, washed with EtOAc, and dried under reduced pressure to obtain N-(cyclohexylmethyl)-N-methyl-4-(4-piperidinyloxy)aniline hydrochloride (820 mg).

Reference Example 60

In an argon stream atmosphere, tris(dibenzylideneacetone)dipalladium (95 mg) was added to a Tol (10 ml) solution containing benzyl 3-iodophenyl ether (1.1 g), tert-butyl 1-piperazinecarboxylate (640 mg), sodium tert-butoxide (500 mg) and 2-biphenylyl(dicyclohexyl)phosphine (70 mg), followed by heating at 80° C. for 1 hour. The reaction solution was cooled, diluted with EtOAc, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=5:1 (v/v)) to obtain a brown solid (950 mg).

The resulting solid (940 mg) was dissolved in EtOAc (5 ml), and a 4 M hydrogen chloride/EtOAc solution (5 ml) was added thereto, followed by stirring overnight at room temperature. The solid precipitated was collected by filtration, washed with EtOAc, and dried under reduced pressure to obtain 1-[3-(benzyloxy)phenyl]piperazine dihydrochloride (840 mg).

Reference Example 61

Diethyl azodicarboxylate (4.8 ml, 40% Tol solution) was dropwise added to a THF (60 ml) solution containing 4-(benzyloxy)-2-chlorophenol (1.7 g, Beilstein Registry No. 6582932), triphenylphosphine (2.8 g) and tert-butyl 4-hydroxypiperidine-1-carboxylate (2.1 g) at 0° C., followed by stirring at room temperature for 24 hours. The reaction solution was diluted with EtOAc. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=5:1 (v/v)) to obtain a white solid (2.3 g).

The resulting compound (1.0 g) was dissolved in EtOAc (10 ml), and a 4 M hydrogen chloride/EtOAc solution (10 ml) was added thereto, followed by stirring overnight at room temperature. The solid precipitated was collected by filtration, washed with EtOAc, and dried under reduced pressure to obtain 4-[4-(benzyloxy)-2-chlorophenoxy]piperidine hydrochloride (690 mg).

Reference Example 62

Thionyl chloride (10 ml) was dropwise added to a DMF (5 ml) solution of sodium 4-hydroxybenzenesulfonate (1.00 g), followed by heating at 65° C. for 3 hours. The reaction solution was cooled and Tol (10 ml) was added thereto. The solvent was evaporated under reduced pressure, water was added, followed by extraction with chloroform. The organic layer was washed with aqueous saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless solid (587 mg).

At 0° C., an acetonitrile (10 ml) solution of the previously-obtained compound (579 mg) was added to an acetonitrile (10 ml) solution containing 1-tert-butoxycarbonylpiperazine (672 mg) and pyridine (0.58 ml), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, Tol (10 ml) was added thereto and azeotroped. Then, water was added, followed by extraction with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless solid (0.41 g).

Potassium carbonate (248 mg) was added to an acetonitrile (20 ml) solution containing the resulting compound (0.41 g) and 1-(bromomethyl)-3-fluorobenzene (340 mg), followed by heating at 80° C. for 3 hours. The solid was removed through filtration, the resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=5:1 (v/v)) to obtain a colorless solid (469 mg).

The resulting compound (460 mg) was dissolved in a mixed solution of EtOAc (5 ml) and THF (5 ml), and 4 M hydrogen chloride/EtOAc solution (20 ml) was added thereto, followed by stirring at 70° C. for 3 hours. Then, the solvent was evaporated under reduced pressure. The residue was dissolved in water, neutralized with an aqueous 1 M sodium hydroxide solution, and the solid formed was dried to obtain 4-{4-[(3-fluorobenzyl)oxy]benzenesulfonyl}piperazine (304 mg).

Reference Example 63

Diethyl azodicarboxylate (3.3 ml, 40% Tol solution) was dropwise added to a THF (30 ml) solution containing 4-(benzyloxy)-3-chlorophenol (1.2 g, Beilstein Registry No. 5527577), triphenylphosphine (1.9 g) and tert-butyl 4-hydroxypiperidine-1-carboxylate (1.5 g) at 0° C., followed by stirring at room temperature for 24 hours. The reaction solution was diluted with EtOAc, and the organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=5:1 (v/v)) to obtain a white solid (1.7 g).

The resulting compound (1.6 g) was dissolved in EtOAc (20 ml), and a 4 M hydrogen chloride/EtOAc solution (15 ml) was added thereto, followed by stirring overnight at room temperature. The solid precipitated was collected by filtration, washed with EtOAc, and dried under reduced pressure to obtain 4-[4-(benzyloxy)-3-chlorophenoxy]piperidine hydrochloride (1.3 g).

Reference Example 64

3-Fluorobenzenesulfonyl chloride (3.2 g) was added to a pyridine (30 ml) solution containing tert-butyl 4-(4-aminophenoxy)-1-piperidinecarboxylate (4.0 g, Beilstein Registry No. 9262581) at 0° C., followed by stirring overnight at room temperature. The solvent was evaporated under reduced pressure, and diluted with chloroform. The organic layer was washed with an aqueous 10% citric acid solution, water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=60:1 (v/v)) to obtain a white solid (5.3 g).

Potassium carbonate (280 mg) and methyl iodide (0.28 ml) were added to an acetonitrile (10 ml) solution containing the resulting compound (700 mg), followed by stirring at 50° C. for 3 hours. The reaction solution was diluted with EtOAc, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=3:1 (v/v)) to obtain a colorless oil (700 mg).

The resulting oil (700 mg) was dissolved in EtOAc (10 ml), and a 4 M hydrogen chloride/EtOAc solution (5 ml) was added thereto, followed by stirring overnight at room temperature. The solid precipitated was collected by filtration, washed with EtOAc, and dried under reduced pressure to obtain 3-fluoro-N-methyl-N-[4-(4-piperidinyloxy)phenyl]benzenesulfonamide hydrochloride (480 mg).

Reference Example 65

1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (630 mg) and 1-hydroxybenzotriazole (440 mg) were added to a DMF (10 ml) solution containing 1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (1.0 g), followed by stirring at room temperature for 1 hour. Then, an aqueous concentrated ammonia (2 ml) was added thereto, followed by stirring at room temperature for 3 hours. Water was added to the reaction solution, and the solid precipitated was collected by filtration, washed with water and dried under reduced pressure to obtain a colorless solid (870 mg).

The resulting solid (860 mg) was dissolved in EtOAc (10 ml), and a 4 M hydrogen chloride/EtOAc solution (5 ml) was added thereto, followed by stirring overnight at room temperature. The precipitated solid was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain benzyl 2-(aminocarbonyl)-1-piperazinecarboxylate hydrochloride (700 mg).

Reference Example 66

Pyridine (1.62 ml) and 4-nitrophenyl chlorocarbonate (2.22 g) were added to an acetonitrile (20 ml) solution containing methyl 4-(hydroxymethyl)benzoate at 0° C., followed by stirring at room temperature for 2 hours. An aqueous 5% citric acid solution was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with an aqueous saturated hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=4:1 (v/v)) to obtain a pale brown powder (2.39 g).

Tert-butyl piperazine-1-carboxylate (1.47 g) was added to an acetonitrile (30 ml) solution containing the resulting compound (2.37 g), followed by stirring at room temperature for 8 hours. The reaction solution was diluted with EtOAc and washed with an aqueous 0.5 M sodium hydroxide solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=2:1 (v/v)) to obtain a colorless solid (3.32 g).

Methanol (0.34 ml) and an aqueous 1 M sodium hydroxide solution (8.52 ml) were added to a THF (30 ml) solution containing the resulting compound (3.30 g), followed by stirring at room temperature for 26 hours. The solvent was evaporated under reduced pressure, an aqueous 1 M hydrochloric acid solution was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was recrystallized from hexane/EtOAc to obtain a colorless powder (2.37 g).

Ammonium chloride (321 mg), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (767 mg), 1-hydroxybenzotriazole (270 mg) and TEA (0.83 ml) were added to a DMF (10 ml) solution containing the resulting compound (729 mg), followed by stirring at room temperature for 3 hours. Water was added to the reaction solution, and the solid precipitated was collected by filtration, and washed with water to obtain a pale brown powder (722 mg).

The resulting compound (700 mg) was dissolved in EtOAc (6 ml), a 4 M hydrogen chloride/EtOAc solution (4.8 ml) was added thereto, followed by stirring at room temperature for 3 hours. The solid formed was collected by filtration, washed with EtOAc, and dried to obtain 4-(aminocarbonyl)benzyl piperazine-1-carboxylate hydrochloride (541 mg).

Reference Example 67

A THF (5 ml) solution containing methyl 4-hydroxybenzoate (460 mg) and diethyl azodicarboxylate (0.71 ml) was dropwise added to a THF (5 ml) solution containing cyclohexylmethanol (510 mg) and triphenylphosphine (1.18 g) at 0° C., followed by stirring at room temperature for 24 hours. An aqueous 1 M sodium hydroxide solution (40 ml) was added to the reaction solution, followed by extraction with EtOAc The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=4:1 (v/v)) to obtain a colorless solid (930 mg).

An aqueous 1 M sodium hydroxide solution (4.4 ml) was added to a methanol (5 ml)/THF (3 ml) solution containing the resulting compound (920 mg), followed by stirring at 50° C. for 6 hours. This was cooled to room temperature, and EtOAc (40 ml) and water (30 ml) were added thereto, followed by stirring. The organic layer was extracted with an aqueous 1 M sodium hydroxide solution. The aqueous layers were combined and made to have a pH of 1 with concentrated hydrochloric acid. Then, the aqueous layer was extracted with chloroform, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from hexane/EtOAc to obtain 4-(cyclohexylmethoxy)benzoic acid (600 mg).

1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (359 mg) and 1-hydroxybenzotriazole (254 mg) were added to a DMF (10 ml) solution containing the resulting compound (370 mg) and tert-butyl 1-piperazinecarboxylate (350 mg), followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, and the solid precipitated was collected by filtration, washed with water and dried under reduced pressure to obtain a colorless solid (610 mg).

The resulting compound (600 mg) was dissolved in EtOAc (6 ml), and a 4 M hydrogen chloride/EtOAc solution (4 ml) was added thereto, followed by stirring overnight at room temperature. The solid precipitated was collected by filtration, washed with EtOAc and dried under reduced pressure to obtain 1-[4-(cyclohexylmethoxy)benzoyl]piperazine hydrochloride (580 mg).

In the same manner as in Reference Example 67, the compounds of Reference Examples 68 to 72 were obtained.

Reference Example 73

At −70° C., a 1.59 M normal-butyllithium/THF solution (14.6 ml) was added to s 2 M dimethylamine/THF solution (11.6 ml), followed by stirring for 10 minutes. This was warmed to 0° C., and 3-chloro-5-hydroxypyridine (1.00 g) was added thereto, followed by stirring overnight at room temperature. Ethanol (15 ml) was added, and the solvent was evaporated under reduced pressure. Water was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain 3-dimethylamino-5-hydroxypyridine (176 mg).

Reference Example 74

Tris-dibenzylideneacetone palladium (21 mg), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (124 mg) and sodium tert-butoxide (160 mg) were added in that order to a Tol (10 ml) solution containing 3-benzyloxy-5-bromopyridine (400 mg) and morpholine (158 mg), followed by heating at 85° C. for 4 hours. The solvent was evaporated under reduced pressure, and the residue was purified through silica gel column chromatography (eluent: chloroform:methanol=20:1 (v/v)) to obtain a colorless oil (372 mg).

10% Palladium-carbon (catalytic amount) was added to an ethanol (20 ml) solution containing the resulting compound (370 mg), and in a hydrogen gas atmosphere, this was stirred at room temperature and under normal pressure for 1.5 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to obtain 5-hydroxy-3-morpholinylpyridine (248 mg).

In the same manner as in Reference Example 74, the compounds of Reference Examples 75 and 76 were obtained.

Reference Example 77

Sodium methoxide (393 mg) was added to a methanol (20 ml) solution containing 5-(benzenesulfonyloxy)-2-(bromomethyl)pyridine (Beilstein Registry No. 7430370, 800 mg), followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: EtOAc) to obtain 6-(methoxymethyl)pyridin-3-ol (200 mg).

Reference Example 78

TEA (0.21 ml) and di-tert-butyl dicarbonate (463 mg) were added in that order to a THF (10 ml) solution of 3-benzyloxy-5-aminopyridine (250 mg), followed by heating at 60° C. for 3 h ours. The solvent was evaporated under reduced pressure, water was added thereto, followed by extraction with EtOAc. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) to obtain a colorless solid (153 mg).

10% Palladium-carbon (catalytic amount) was added to an ethanol (20 ml) solution containing the resulting compound (240 mg), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 1.5 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to obtain tert-butyl (5-hydroxypyridin-3-yl)carbamate (167 mg).

Reference Example 79

At 0° C., a THF (10 ml) suspension of sodium hydride (60% oil mixture, 139 mg) was added to a THF (10 ml) solution of methyl diethylphosphonoacetate (732 mg), followed by stirring for 15 minutes. Then, 5-(benzyloxy)nicotinaldehyde (495 mg) was added, followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless solid (680 mg).

10% Palladium-carbon (catalytic amount) was added to an ethanol (20 ml) solution containing the resulting compound (330 mg), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 2 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to obtain methyl 3-(5-hydroxypyridin-3-yl)propanoate (150 mg).

Reference Example 80

At −78° C., a THF (30 ml) solution of methyl 5-(benzyloxy)nicotinate (3.52 g) was added to a THF (100 ml) suspension of lithium aluminium hydride (1.49 g), followed by stirring for 15 minutes and then stirring at room temperature for 2 hours. The reaction solution was cooled to 0° C., and then water (1.49 ml), an aqueous 15% sodium hydroxide solution (1.49 ml) and water (4.47 ml) were added thereto in that order. The solid was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain a colorless solid (1.41 g).

Tert-butyl bromoacetate (609 mg), tetrabutylammonium hydrogensulfate (35 mg) and an aqueous 50% sodium hydroxide solution (2 ml) were added in that order to a benzene (20 ml) solution containing the resulting compound (450 mg), followed by stirring overnight at room temperature. This was neutralized with an aqueous 1 M hydrochloric acid, followed by extraction with EtOAc. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=6:4 (v/v)) to obtain a colorless oil (576 mg).

10% palladium-carbon (catalytic amount) was added to an ethanol (20 ml) solution containing the resulting compound (570 mg), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 1 hour. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol=15:1 (v/v)) to obtain tert-butyl[(5-hydroxypyridin-3-yl)methoxy]acetate (400 mg).

Reference Example 81

Pentamethylbenzene (826 mg) was added to a TFA (10 ml) solution containing methyl (2E)-3-[5-(benzyloxy)pyridin-3-yl]acrylate (300 mg), followed by stirring overnight at 60° C. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain tert-butyl (5-hydroxypyridin-3-yl)acetate (180 mg).

Reference Example 82

Diisopropylethylamine (2.05 ml) and methoxymethyl chloride (0.89 ml) were added in that order to a THF (60 ml) solution of methyl 3-hydroxynicotinate (1.50 g), and then stirred overnight at room temperature. The solvent was evaporated under reduced pressure, water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless oil (2.01 g).

At −78° C., a THF (20 ml) solution of the resulting compound (1.98 g) was added to a THF (50 ml) suspension of lithium aluminium hydride (838 mg), followed by stirring for 30 minutes and then stirring at room temperature for 2 hours. The reaction solution was cooled to 0° C., and water (0.84 ml), an aqueous 15% sodium hydroxide solution (0.84 ml) and water (2.52 ml) were added thereto in that order. The solid was removed by filtration, and the resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: EtOAc) to obtain a colorless oil (838 mg).

Acetic anhydride (1.39 ml) was added to a pyridine (10 ml) solution containing the resulting compound (828 mg), followed by stirring at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, Tol (10 ml) was added thereto and azeotroped to obtain a colorless oil (1.01 g).

4 M hydrogen chloride/dioxane solution (3.58 ml) was added to a dioxane (10 ml) solution of the resulting compound (1.01 g), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure to obtain (5-hydroxypyridin-3-yl)methyl acetate hydrochloride (973 mg).

Reference Example 95

Triphenylphosphine (2.8 g) was added to a Tol (50 ml) solution of 3-cyanobenzyl bromide (2.0 g), followed by stirring at 80° C. for 5 hours. This was cooled to room temperature, and the precipitated solid was collected by filtration, and washed with Tol. This was dried under reduced pressure to obtain (3-cyanobenzyl)(triphenyl)phosphonium bromide (3.4 g).

Under ice cooling, sodium hydride (60% oil, 141 mg) was added to a DMF (20 ml) solution of (3-cyanobenzyl)(triphenyl)phosphonium bromide (1.6 g) and tert-butyl 4-formyl-1-piperidinecarboxylate (0.75 g), followed by stirring overnight at room temperature. The reaction liquid was diluted with EtOAc, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=6:1 (v/v)) to obtain an oil. 10% Palladium-carbon (100 mg) was added to an EtOAc (30 ml) solution of the resulting oil, followed by stirring in a hydrogen stream atmosphere for 2 hours. The catalyst was removed with Celite, and the solvent was concentrated to obtain an oil. The resulting oil was dissolved in EtOAc (10 ml), and 4 M hydrogen chloride/EtOAc solution (5 ml) was added thereto, then stirred at room temperature for 6 hours, and then concentrated. The resulting solid was washed with ether and dried under reduced pressure to obtain 3-[2-(4-piperidinyl)ethyl]benzonitrile hydrochloride (506 mg).

In the same manner as in Reference Example 95, the compounds of Reference Examples 96 to 101 were obtained.

Reference Example 102

Triphenylphosphine (85.8 g) was added to a Tol (400 ml) solution of methyl 3-bromomethylbenzoate (50.0 g), followed by stirring at 80° C. for 10 hours. After this was cooled to room temperature, the crystal precipitated was collected by filtration and washed with Tol. This was dried under reduced pressure to obtain (3-methoxycarbonylbenzyl)(triphenyl)phosphonium bromide (107.6 g).

Under ice cooling, potassium tert-butoxide (22.5 g) was added to a DMF (250 ml) solution of (3-methoxycarbonylbenzyl)(triphenyl)phosphonium bromide (84.6 g), followed by stirring at room temperature for 30 minutes. Then, a DMF (50 ml) solution of tert-butyl 4-formyl-1-piperidinecarboxylate (30.6 g) was added to it under ice cooling, and then stirred overnight at room temperature. Acetic acid (11.5 ml) was added to the reaction liquid, followed by stirring at room temperature for 1 hour. Then, this was diluted with EtOAc, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=7:1 (v/v)). The residue was dissolved in EtOAc, activated charcoal was added thereto, followed by stirring at room temperature for 2 hours. Activated charcoal was removed with Celite, and the solvent was evaporated under reduced pressure to obtain a colorless oil.

10% Palladium-carbon (4.58 g) was added to an EtOAc (400 ml) solution of the resulting oil, followed by stirring in a hydrogen stream atmosphere for 2 hours. The catalyst was removed with Celite, and the solvent was concentrated to obtain tert-butyl 4-{2-[3-(methoxycarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (45.4 g).

In the same manner as in Reference Example 102, the compound of Reference Example 103 was obtained.

Reference Example 104

Aqueous 1 M sodium hydroxide solution (196 ml) was added to a THF (200 ml)/methanol (50 ml) mixed solution of tert-butyl 4-{2-[3-(methoxycarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (45.4 g), followed by stirring at 60° C. for 2 hours. The organic solvent was evaporated under reduced pressure, and under ice cooling, 0.5 M hydrochloric acid (400 ml) was added to the residue. The reaction liquid was diluted with EtOAc, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}benzoic acid (43.5 g) was obtained.

In the same manner as in Reference Example 104, the compound of Reference Example 105 was obtained.

Reference Example 106

3-{2-[1-(Tert-butoxycarbonyl)-4-piperidinyl]ethyl}benzoic acid (17.8 g) was dissolved in DMF (200 ml), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (15.4 g) and 1-hydroxybenzotriazole (10.8 g) were added thereto, followed by stirring at room temperature for 2 hours. Ammonium chloride (8.57 g) and TEA (22.3 ml) were added to the reaction liquid, followed by stirring overnight at room temperature. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and the precipitated crystal was collected by filtration and dried to obtain tert-butyl 4-{2-[3-(aminocarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (10.8 g).

In the same manner as in Reference Example 106, the compounds of Reference Examples 107 to 118 were obtained.

Reference Example 119

Tert-butyl 4-[2-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylate (280 mg), carbon tetrabromide (247 mg) and 2,6-lutidine (103 μl) were dissolved in dichloromethane (5.6 ml), and under ice cooling, triphenylphosphine (195 mg) was added thereto, followed by stirring at room temperature for 3 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=3:7 (v/v)) to obtain tert-butyl 4-{2-[4-(1-aziridinylcarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (136 mg) as a colorless oil.

Reference Example 120

Tert-butyl 4-{2-[3-(aminocarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (13.8 g) was dissolved in EtOAc (200 ml), and 4 M hydrogen chloride/EtOAc solution (130 ml) was added thereto, followed by stirring at room temperature for 4 hours, and then concentrated. Acetonitrile was added to the resulting residue, followed by heating, and the precipitated crystal was collected by filtration, washed with EtOAc, and dried under reduced pressure to obtain 3-[2-(4-piperidinyl)ethyl]benzamide hydrochloride (11.2 g).

In the same manner as in Reference Example 120, the compounds of Reference Examples 121 to 139 were obtained.

Reference Example 140

In an argon stream atmosphere, sodium carbonate (0.43 g) and tetrakis(triphenylphosphine)palladium (80 mg) were added to a Tol (6 ml)/water (2 ml) solution of tert-butyl 4-[2-(3-bromophenyl)ethyl]-1-piperidinecarboxylate (0.50 g) and phenylboronic acid (0.20 g), followed by heating with stirring at 100° C. for 7 hours. This was cooled to room temperature, diluted with EtOAc, and washed with aqueous saturated sodium hydrogencarbonate solution. This was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl 4-[2-(3-biphenyl)ethyl]-1-piperidinecarboxylate (0.41 g).

4 M hydrogen chloride/EtOAc (1.5 ml) was added to an EtOAc (4 ml) solution of tert-butyl 4-[2-(3-biphenyl)ethyl]-1-piperidinecarboxylate (0.41 g), followed by stirring overnight at room temperature. The precipitated crystal was collected by filtration, washed with EtOAc/hexane and dried under reduced pressure to obtain 4-[2-(3-biphenyl)ethyl]piperidine hydrochloride (0.31 g).

In the same manner as in Reference Example 140, the compounds of Reference Examples 141 and 142 were obtained.

Reference Example 143

Under ice cooling, di-tert-butyl dicarbonate (2.6 g) was added to a dichloromethane (50 ml) solution of 4,4′-(1,3-propane-diyl)dipiperidine (5.0 g), followed by stirring overnight at room temperature. The reaction liquid was diluted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol:aqueous concentrated ammonia=4:1:0.1 (v/v)) to obtain tert-butyl 4-[3-(4-piperidinyl)propyl]-1-piperidinecarboxylate (2.2 g).

In an argon atmosphere, sodium tert-butoxide, (0.52 g), tris(dibenzylideneacetone)dipalladium (100 mg) and 2-(dicyclohexylphosphino)biphenyl (76 mg) were added to a Tol (22 ml) solution of 2-chloro-6-methylpyridine (0.56 g) and tert-butyl 4-[3-(4-piperidinyl)propyl]-1-piperidinecarboxylate (1.1 g), followed by heating with stirring at 100° C. for 1 hour. This was cooled to room temperature, diluted with EtOAc, and washed with aqueous saturated sodium hydrogencarbonate solution. This was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl 4-{3-[1-(6-methyl-2-pyridinyl)-4-piperidyl]propyl}-1-piperidinecarboxylate (1.3 g).

4 M hydrogen chloride/EtOAc (10 ml) was added to an EtOAc (25 ml) solution of tert-butyl 4-{3-[1-(6-methyl-2-pyridinyl)-4-piperidinyl]propyl}-1-piperidinecarboxylate (1.3 g), followed by stirring overnight at room temperature. The reaction liquid was concentrated, then 2-propanol/diethyl ether was added thereto, followed by stirring. The precipitated solid was collected by filtration, and dried under reduced pressure to obtain 2-methyl-6-{4-[3-(4-piperidinyl)propyl]-1-piperidyl}pyridine dihydrochloride (1.1 g).

In the same manner as in Reference Example 143, the compounds of Reference Examples 144 and 145 were obtained.

Reference Example 146

Methanesulfonyl chloride (2.7 ml) was dropwise added to a methylene chloride (200 ml) solution of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (8.00 g) and TEA (4.8 ml) at 0° C., followed by stirring overnight at room temperature. The reaction liquid was washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: EtOAc:hexane=1:3 (v/v)) to obtain tert-butyl 4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1-carboxylate (10.1 g).

A DMI (20 ml) suspension of tert-butyl 4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1-carboxylate (1.00 g), 1-piperazin-1-yl-isoquinoline dihydrochloride (980 mg), cesium carbonate (1.02 g) and sodium iodide (467 mg) was stirred at 140° C. for 1 hour. EtOAc was added to the reaction liquid, washed with water and aqueous saturated sodium hydrogencarbonate solution in that order, then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) to obtain tert-butyl 4-[3-(4-isoquinolin-1-ylpiperazin-1-yl)propyl]piperidine-1-carboxylate (1.07 g) as a pale yellow oil.

4 M hydrogen chloride/EtOAc solution (5.0 ml) was dropwise added to an EtOAc (15 ml) solution of tert-butyl 4-[3-(4-isoquinolin-1-ylpiperazin-1-yl)propyl]piperidine-1-carboxylate (1.44 g), followed by stirring overnight. The solvent was evaporated, the solid was washed with EtOAc and collected by filtration to obtain 1-[4-(3-piperidin-4-ylpropyl)piperazin-1-yl]isoquinoline dihydrochloride (1.32 g) as a white solid.

In the same manner as in Reference Example 146, the compound of Reference Example 154 was obtained.

Reference Example 147

4-Nitrophenyl chloroformate (7.0 g) was added to a dichloromethane (100 ml) solution of methyl 5-hydroxynicotinate (5.3 g) and diisopropylethylamine (6.1 ml), followed by stirring at room temperature for 1 hour. The reaction liquid was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting solid was washed with EtOAc/hexane and dried under reduced pressure to obtain methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (8.4 g).

In the same manner as in Reference Example 147, the compound of Reference Example 148 was obtained.

Reference Example 151

A DMF (15 ml) solution of 3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl]benzoic acid (1.25 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (863 mg) and 1-hydroxybenzotriazole (608 mg) was stirred at room temperature for 1 hour, and then a TEA (1.6 ml) solution of 2-bromoethylamine hydrobromide (2.30 g) was added thereto, followed by stirring overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, followed by extraction with EtOAc, then washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain a crude product of tert-butyl 4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylate.

4 M hydrogen chloride/EtOAc solution (5 ml) was added to an EtOAc (15 ml) solution of the crude tert-butyl 4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylate at room temperature, followed by stirring overnight. The solvent was evaporated under reduced pressure to obtain N-(2-bromoethyl)-3-(2-piperidin-4-ylethyl)benzamide hydrochloride (1.27 g) as a white solid.

TEA (0.90 ml) was dropwise added to an acetonitrile (30 ml) suspension of N-(2-bromoethyl)-3-(2-piperidin-4-ylethyl)benzamide hydrochloride (1.20 g) and methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (1.02 g), followed by stirring overnight at room temperature. The reaction solvent was evaporated under reduced pressure, then aqueous saturated sodium hydrogencarbonate solution was added thereto, extracted with EtOAc, and dried over anhydrous magnesium sulfate. This was filtered, the solvent was evaporated, and the residue was purified two times through silica gel column chromatography (basic silica with eluent: hexane:EtOAc=1:2 (v/v), next neutral silica with eluent: chloroform:methanol=19:1 (v/v)) to obtain methyl 5-[{(4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidin-1-yl}carbonyl)oxy]nicotinate (762 mg) as a white powder.

A DMF (10 ml) suspension of methyl 5-[{(4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidin-1-yl}carbonyl)oxy]nicotinate (750 mg), potassium carbonate (300 mg) and potassium iodide (361 mg) was stirred at 80° C. for 1 hour. The reaction liquid was left cooled, then EtOAc was added thereto, washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1 (v/v)) to obtain methyl 5-{[(4-{2-[3-(aziridin-1-ylcarbonyl)phenyl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (630 mg) as a colorless oil.

Reference Example 152

Under ice cooling, diphenylphosphorylazide (540 mg) was added to a Tol solution (10 ml) of 3-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl]benzoic acid (600 mg) and TEA (0.3 ml), followed by stirring at room temperature for 2 hours. EtOAc was added to the reaction solution, washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a colorless oil (630 mg). A Tol solution (10 ml) of the resulting oil (400 mg) was stirred at 110° C. for 1 hour. This was cooled to room temperature, and aqueous 30% ammonia solution (0.2 ml) was added thereto, followed by stirring at room temperature for 15 hours. EtOAc was added to the reaction solution, then washed with aqueous 1 N hydrochloric acid solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=95:5 (v/v)) to obtain tert-butyl 4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidinecarboxylate (227 mg).

4 M hydrogen chloride/EtOAc (4 ml) was added to an EtOAc (9 ml) solution of tert-butyl 4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidinecarboxylate (227 mg), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure to obtain 1-{3-[2-(4-piperidyl)ethyl]phenyl}urea hydrochloride (185 mg).

Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (228 mg) was added to an acetonitrile (5 ml) solution of 1-{3-[2-(4-piperidinyl)ethyl]phenyl}urea hydrochloride (185 mg) and TEA (0.2 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with EtOAc, washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain methyl 5-({[4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidyl]carbonyl}oxy)nicotinate (183 mg).

In the same manner as in Reference Example 152, the compound of Reference Example 153 was obtained.

Reference Example 155

Tert-butyl 4-ethynylpiperidine-1-carboxylate (12.5 g) and iodobenzene (12.8 g) was dissolved in THF:TEA=1:1 (v/v) mixed solvent (125 ml), then at room temperature, copper iodide (455 mg) and palladium tetrakistriphenylphosphine complex (1.38 g) were added thereto in that order, followed by stirring overnight at room temperature. The solvent was evaporated, EtOAc was added to it, and washed with aqueous 1 M hydrochloric acid solution, water and saturated brine in that order. This was dried over magnesium sulfate, and the solvent was evaporated to obtain a light brown oil. This was purified by silica gel column chromatography (eluent: hexane:EtOAc=19:1 (v/v)) to obtain tert-butyl 4-(phenylethynyl)piperidine-1-carboxylate (15.5 g) as a light brown oil.

4 M hydrogen chloride/EtOAc solution (70 ml) was added to tert-butyl 4-(phenylethynyl)piperidine-1-carboxylate (7.0 g), followed by stirring at room temperature for 30 minutes. The solvent was evaporated to obtain 4-(phenylethynyl)piperidine hydrochloride (5.4 g) as a white powder.

Example 1

3-Hydroxypyridine (400 mg), TEA (1.17 ml) and DMAP (catalytic amount) were added in that order to a THF (10 ml) solution containing piperidine-1-carbonyl chloride (745 mg), and then heated at 60° C. for 5 hours. The reaction solution was cooled, then water (3 ml) was added thereto, and extracted with EtOAc. The extract was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) to obtain a colorless oil. The resulting oil was dissolved in ethanol, and an ethanol solution of oxalic acid (378 mg) added thereto to obtain a colorless powder. This was recrystallized from hexane/ethanol to obtain (pyridin-3-yl)piperidine-1-carboxylate oxalate (761 mg).

Example 2

A methylene chloride (20 ml) solution containing 3-hydroxypyridine (568 mg) and pyridine (724 μl) was dropwise added to a methylene chloride (25 ml) solution containing triphosgene (590 mg), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, the residue was dissolved in pyridine (30 ml), then the compound (1.2 g) obtained in Reference Example 22 was added thereto, followed by heating at 70° C. for 4 hours. The reaction solution was concentrated under reduced pressure, then chloroform and aqueous sodium hydrogencarbonate solution was added thereto, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:2 (v/v)) to obtain a colorless powder. This was recrystallized from hexane/EtOAc to obtain (pyridin-3-yl) 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (861 mg).

In the same manner as in Example 2, the compounds of Examples 3 to 118, 389 to 391, 416 and 417 and Reference Examples 83 to 93 were obtained.

Example 119

A methylene chloride (20 ml) solution containing 3-hydroxypyridine (1.43 g) and pyridine (1.46 ml) was dropwise added to a methylene chloride (30 ml) solution containing triphosgene (1.48 g), followed by stirring at room temperature for 1 hour. A methylene chloride (5 ml) solution containing tert-butyl 1-piperazinecarboxylate (2.0 g) and pyridine (0.97 ml) was dropwise added to the reaction solution, then pyridine (20 ml) was added thereto, followed by heating at 70° C. for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with EtOAc, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified through basic silica gel column chromatography (eluent: hexane:EtOAc=4:1 (v/v)) to obtain a colorless solid (3.0 g).

The resulting compound (3.0 g) was dissolved in EtOAc (20 ml)/2-propanol (10 ml), then 4 M hydrogen chloride/EtOAc solution (10 ml) was added thereto, followed by stirring overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting solid was washed with EtOAc and dried under reduced pressure to obtain 3-pyridyl 1-piperazinecarboxylate dihydrochloride (2.66 g).

1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (150 mg), 1-hydroxybenzotriazole (110 mg) and diisopropylethylamine (0.23 ml) were added to a DMF (5 ml) solution containing the resulting compound (190 mg) and 4-(cyclooctylmethoxy)benzoic acid (176 mg) prepared from cyclooctylmethanol with reference to Reference Example 70, followed by stirring overnight at room temperature. The reaction solution was diluted with EtOAc, the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from EtOAc/hexane to obtain 3-pyridyl 4-[4-(cyclooctylmethoxy)benzoyl]-1-piperazinecarboxylate (240 mg).

In the same manner as in Example 119, the compounds of Examples 120 to 136 were obtained.

Example 137

Potassium tert-butoxide (810 mg) was added to a DMF (10 ml) solution containing 6-chloronicotinonitrile (1.0 g) and 3-chlorobenzyl alcohol (1.0 g), followed by stirring overnight at room temperature. Water was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water and hexane in that order, and dried under reduced pressure to obtain a brown solid (1.3 g).

An aqueous 5 M sodium hydroxide solution (10 ml) was added to an ethanol (10 ml) solution containing the resulting compound (1.3 g), followed by stirring at 100° C. for 4 hours. After this was cooled to room temperature, 1 N hydrochloric acid (56 ml) was added thereto, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to obtain a colorless solid (0.82 g).

1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (150 mg), 1-hydroxybenzotriazole (110 mg) and diisopropylethylamine (0.23 ml) were added to a DMF (5 ml) solution containing the resulting compound (176 mg) and 3-pyridyl 1-piperazinecarboxylate dihydrochloride (166 mg), followed by stirring overnight at room temperature. The reaction solution was diluted with EtOAc, the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified through basic silica gel column chromatography (eluent: hexane:EtOAc=1:2 (v/v)) to obtain a colorless oil (140 mg).

Oxalic acid (35 mg) was added to a 2-propanol solution containing the resulting compound (140 mg), followed by stirring for 30 minutes. The precipitated solid was collected by filtration, washed with 2-propanol/hexane, and dried under reduced pressure to obtain 3-pyridyl 4-({6-[(3-chlorobenzyl)oxy]-3-pyridyl}carbonyl)-1-piperazinecarboxylate 0.5-oxalate (120 mg).

In the same manner as in Example 137, the compound of Example 138 was obtained.

Example 139

Potassium carbonate (1.04 g) and ethyl bromoacetate (0.610 ml) were added to an acetonitrile (15 ml) solution containing 4-hydroxybenzamide (686 mg), followed by heating at 80° C. for 2 hours. The reaction solution was cooled, water (45 ml) was added thereto, and the precipitated solid was collected by filtration, washed with water and dried to obtain ethyl[4-(aminocarbonyl)phenoxy]acetate (893 mg) as pale brown powder.

The resulting compound (870 mg) was dissolved in THF (10 ml), and ethanol (0.274 ml) and an aqueous 1 M sodium hydroxide solution (4.68 ml) were added thereto, followed by stirring at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, acidified with an aqueous 1 M hydrochloric acid solution, and the precipitated solid was collected by filtration and dried to obtain a pale brown powder [4-(aminocarbonyl)phenoxy]acetic acid (714 mg).

TEA (0.251 ml), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (259 mg), 1-hydroxybenzotriazole (122 mg) and the above-produced compound [4-(aminocarbonyl)phenoxy]acetic acid (184 mg) were added to a DMF (5 ml) solution containing 3-pyridyl 1-piperidinecarboxylate dihydrochloride (252 mg) obtained in the method of Example 121, followed by stirring at room temperature for 5 hours. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=95:5 (v/v)), and the resulting solid was recrystallized from EtOAc/acetonitrile to obtain pyridin-3-yl 4-{[4-(aminocarbonyl)phenoxy]acetyl}piperidine-1-carboxylate (274 mg).

In the same manner as in Example 139, the compounds of Examples 140 and 141 were obtained.

Example 142

TEA (0.23 ml) and benzenesulfonyl chloride (0.075 ml) were added to a dichloromethane (5 ml) solution containing 3-pyridyl 1-piperazinecarboxylate dihydrochloride (150 mg), followed by stirring overnight at room temperature. The reaction solution was diluted with chloroform, the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform), and the resulting solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-(phenylsulfonyl)-1-piperazinecarboxylate (130 mg).

In the same manner as in Example 142, the compound of Example 143 was obtained.

Example 144

Benzyl chloroformate (91 mg) was added to a pyridine (3 ml) solution containing 3-pyridyl 1-piperazinecarboxylate dihydrochloride (150 mg), followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with EtOAc, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was diluted with 2-propanol (3 ml), and toluenesulfonic acid hydrate (100 mg) was added thereto, followed by stirring. The crystal precipitated was collected by filtration and recrystallized from 2-propanol to obtain benzyl 3-pyridyl 1,4-piperazinedicarboxylate tosylate (98 mg).

In the same manner as in Example 144, the compounds of Examples 145 and 146 were obtained.

Example 147

10% Palladium-carbon (catalytic amount) was added to a THF (20 ml)/2-propanol (20 ml) solution containing 3-pyridyl 4-[(4-benzyloxy)benzoyl]-1-piperazinecarboxylate (1.3 g), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 12 hours. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting solid was recrystallized from EtOAc/hexane to obtain 3-pyridyl 4-(4-hydroxybenzoyl)-1-piperazinecarboxylate (950 mg).

A THF (5 ml) solution containing 3-pyridyl 4-(4-hydroxybenzoyl)-1-piperazinecarboxylate (300 mg) and diethyl azodicarboxylate (0.62 ml, 40% Tol solution) was dropwise added to a THF (5 ml) solution containing 3-chlorobenzyl alcohol (200 mg) and triphenylphosphine (360 mg), at 0° C., followed by stirring at room temperature for 3 days. The reaction solution was diluted with chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=95:5 (v/v)), and the resulting solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-{4-[(3-chlorobenzoyl)oxy]benzyl}-1-piperazinecarboxylate (260 mg).

In the same manner as in Example 147, the compounds of Examples 148 to 166 were obtained.

Example 167

Potassium carbonate (270 mg) was added to an acetonitrile (10 ml) solution containing 3-pyridyl 4-(4-hydroxybenzoyl)-1-piperazinecarboxylate (530 mg) and methyl 3-(bromomethyl)benzoate (450 mg), followed by stirring at 80° C. for 1 hour. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:4 (v/v)) to obtain a colorless solid (470 mg).

The resulting solid (100 mg) was recrystallized from EtOAc to obtain 3-pyridyl 4-(4-{[3-(methoxycarbonyl)benzyl]oxy}benzoyl)-1-piperazinecarboxylate (88 mg).

Example 168

4-Ethyl 1-pyridin-3-yl piperidine-1,4-dicarboxylate (0.732 g) was dissolved in THF (15 ml) and ethanol (8.0 ml), and under ice cooling, an aqueous 1 M sodium hydroxide solution (3.9 ml) was dropwise added thereto. This was stirred at room temperature for 2 hours, and neutralized with 1 M hydrochloric acid (0.5 ml). The reaction liquid was concentrated under reduced pressure, methanol was added to the residue, and the precipitated salt was removed through suction filtration. The filtrate was concentrated to obtain 1-[(pyridin-3-yloxy)carbonyl]piperidine-4-carboxylic acid (0.727 g) as a colorless solid.

The resulting compound (0.60 g) was dissolved in dimethylformamide (10 ml), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.93 g), 1-hydroxybenzotriazole (0.51 g) and cyclohexanemethylamine (0.43 g) were added thereto, followed by stirring at room temperature for 15 hours. Water was added to the reaction solution, followed by further stirring for 1 hour. Then, sodium hydrogencarbonate solution was added thereto, followed by Extraction with EtOAc. The organic layer was washed with 0.5 M hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:4 (v/v)) to obtain a colorless powder (0.69 g). This was recrystallized from ethanol and hexane to obtain (pyridin-3-yl) 4-{[(cyclohexylmethyl)amino]carbonyl}piperidine-1-carboxylate (261 mg).

In the same manner as in Example 168, the compounds of Examples 169 to 192, 383 to 388 and Reference Example 94 were obtained.

Example 193

3-Pyridinyl chlorocarbonate (330 mg) was added to a pyridine (10 ml) solution containing 1-benzyl 2-methyl-1,2-piperazinedicarboxylate (660 mg, Beilstein Registry No. 4236331), followed by stirring at 80° C. for 7 hours. The reaction solution was concentrated under reduced pressure, diluted with chloroform, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified through basic silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) to obtain a colorless oil (700 mg).

An aqueous 1 M sodium hydroxide solution (1.2 ml) was added to a THF (5 ml) solution containing the resulting compound (430 mg), followed by stirring at 50° C. for 3 hours. Aqueous 1 M sodium hydroxide solution (0.8 ml) was added thereto, and further heated at 50° C. for 1 hours, then cooled to room temperature, and 1 N hydrochloric acid (2 ml) was added thereto. The reaction solution was extracted with EtOAc, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the precipitated solid was washed with EtOAc/hexane, and dried under reduced pressure to obtain 1-[(benzyloxy)carbonyl]-4-[(3-pyridyloxy)carbonyl]-2-piperidinecarboxylic acid (140 mg).

In the same manner as in Example 193, the compounds of Examples 194 and 195 were obtained.

Example 196

Pyridin-3-yl 4-({[2-(methylamino)phenyl]amino}carbonyl)piperidine-1-carboxylate (0.41 g) was dissolved in acetic acid (10 ml), followed by heating under reflux for 2 hours. The solvent was evaporated, and the residue was recrystallized from methanol and diethyl ether to obtain (pyridin-3-yl) 4-(1-methyl-1H-benzimidazol-2-yl)piperidine-1-carboxylate (307 mg).

Example 197

Pyridin-3-yl 4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate (0.249 g) was dissolved in THF (5.0 ml), and under ice cooling, 4 M hydrogen chloride/EtOAc solution (2.10 ml) was added thereto, followed by stirring at room temperature for 24 hours. The reaction solution was concentrated to dryness to obtain pyridin-3-yl 4-aminopiperidine-1-carboxylate dihydrochloride (0.280 g).

The resulting compound (0.28 g) was dissolved in dimethylformamide (10 ml), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.28 g), 1-hydroxybenzotriazole (0.16 g), TEA (0.54 ml) and 6-phenylhexanoic acid (0.18 g) were added thereto, followed by stirring at room temperature for 15 hours. Water was added to the reaction solution and further stirred for 1 hour. Then, sodium hydrogencarbonate solution was added thereto, followed by extraction with EtOAc. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: EtOAc) to obtain a colorless powder. This was recrystallized from methanol and diethyl ether to obtain (pyridin-3-yl) 4-[(6-phenylhexanoyl)amino]piperidine-1-carboxylate (108 mg).

Example 198

10% Palladium-carbon (catalytic amount) was added to a THF (75 ml)/2-propanol (75 ml) solution containing 3-pyridyl 4-[3-(benzyloxy)phenoxy]-1-piperidinecarboxylate (4.0 g), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc/hexane, and dried under reduced pressure to obtain 3-pyridyl 4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (2.2 g).

Example 199

10% Palladium-carbon (catalytic amount) was added to a THF (75 ml)/2-propanol (75 ml) solution containing 3-pyridyl 4-[4-(benzyloxy)phenoxy]-1-piperidinecarboxylate (3.7 g), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc/hexane, and dried under reduced pressure to obtain 3-pyridyl 4-(4-hydroxyphenoxy)-1-piperidinecarboxylate (2.4 g).

Example 200

Diethyl azodicarboxylate (0.35 ml, 40% Tol solution) was dropwise added to a THF (5 ml) solution containing 3-pyridyl 4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (160 mg), cyclohexylmethanol (87 mg) and triphenylphosphine (200 mg), at 0° C., followed by stirring at room temperature for 24 hours. The reaction solution was diluted with chloroform, washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)). The resulting oil was dissolved in EtOAc (5 ml), 4 M hydrogen chloride/EtOAc solution (1 ml) was added thereto, followed by stirring at room temperature. The solvent was evaporated under reduced pressure, and the precipitated solid was washed with EtOAc/2-propanol and dried under reduced pressure to obtain 3-pyridyl 4-[3-(cyclohexylmethoxy)phenoxy]-1-piperidinecarboxylate hydrochloride (94 mg).

In the same manner as in Example 200, the compounds of Examples 201 to 205 were obtained.

Example 206

Diethyl azodicarboxylate (0.35 ml, 40% Tol solution) was dropwise added to a THF (5 ml) solution containing 3-pyridyl 4-(4-hydroxyphenoxy)-1-piperidinecarboxylate (160 mg), 3-chlorobenzyl alcohol (110 mg) and triphenylphosphine (200 mg) at 0° C., followed by stirring at room temperature for 24 hours. The reaction solution was diluted with chloroform, washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:3 (v/v)). The resulting oil was dissolved in EtOAc (5 ml), and 4 M hydrogen chloride/EtOAc solution (1 ml) was added thereto, followed by stirring at room temperature. The solvent was evaporated under reduced pressure, and the precipitated solid was recrystallized from EtOAc/2-propanol to obtain 3-pyridyl 4-{4-[(3-chlorobenzyl)oxy]phenoxy}-1-piperidinecarboxylate hydrochloride (45 mg).

In the same manner as in Example 206, the compounds of Examples 207 to 212 were obtained.

Example 213

10% Palladium-carbon (catalytic amount) was added to an ethanol (100 ml) solution containing methyl 5-[({4-[4-(benzyloxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinate, and in a hydrogen gas atmosphere, this was stirred overnight at room temperature under normal pressure. The catalyst was removed by filtration, the resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=15:1 (v/v)) to obtain a colorless oil (1.08 g).

2.2 M diethyl azodicarboxylate (1.01 ml) and triphenylphosphine (581 mg) were added to a THF (20 ml) solution containing the resulting compound (450 mg) and 3-cyclohexyl-1-propanol (315 mg), followed by heating at 50° C. for 22 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=2:1 (v/v)) to obtain methyl 5-[({4-[4-[(3-cyclohexylpropoxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinate (242 mg).

In the same manner as in Example 213, the compounds of Examples 214 to 216 were obtained.

Example 217

10% Palladium-carbon (catalytic amount) was added to a THF (10 ml) solution containing 5-[({4-[4-(benzyloxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid (200 mg), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 3 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to obtain 5-[({4-[4-(hydroxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid (55 mg).

Example 218

The compound (4.0 g) of Example 29, obtained in the same method as in Example 2, was dissolved in THF (30 ml) and methanol (15 ml), and under ice cooling, an aqueous 1 M sodium hydroxide solution (12 ml) was dropwise added thereto. This was stirred at room temperature for 30 minutes, and then under ice cooling, this was neutralized with 1 M hydrochloric acid (12 ml). The colorless solid precipitated was collected by filtration to obtain 5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}nicotinic acid (3.52 g).

In the same manner as in Example 218, the compounds of Examples 219 to 224 and Examples 226 to 243 were obtained.

Example 225

A methylene chloride (30 ml) solution containing methyl 5-hydroxynicotinate (2.20 g) and pyridine (4 ml) was dropwise added to a methylene chloride (50 ml) solution containing triphosgene (1.56 g), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, the residue was dissolved in pyridine (50 ml), and 4-(2-phenylethyl)piperidine hydrochloride (2.70 g) was added thereto, followed by heating overnight at 80° C. The reaction solution was concentrated under reduced pressure, then EtOAc and an aqueous sodium hydrogencarbonate solution were added thereto. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) to obtain a colorless powder. This was recrystallized from hexane/EtOAc to obtain methyl 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinate (3.95 g).

Methyl 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinate (3.95 g) was dissolved in THF (32 ml) and methanol (16 ml), and under ice cooling, aqueous 1 M sodium hydroxide solution (16 ml) was dropwise added thereto. This was stirred at room temperature for 30 minutes, and under ice cooling, this was neutralized with 1 M hydrochloric acid (16 ml). The colorless solid precipitated was collected by filtration, and recrystallized from methanol/water to obtain 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinic acid (3.70 g).

Example 244

The compound of Example 219, 5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}nicotinic acid (0.50 g) was dissolved in DMF (8.0 ml), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.38 g), 1-hydroxybenzotriazole (0.22 g) and glycine tert-butyl ester (0.21 g) were added thereto, followed by stirring at room temperature for 15 hours. Water was added to the reaction solution, followed by stirring for 1 hours. Then, sodium hydrogencarbonate solution was added thereto, followed by extraction with EtOAc. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) to obtain a colorless oil (0.444 g).

The resulting compound (0.444 g) was dissolved in methylene chloride (5.0 ml), and under ice cooling, TFA (1.15 ml) was added thereto. This was stirred at that temperature for 24 hours, and then the reaction liquid was concentrated to obtain a yellow solid. This was recrystallized from ethanol and diethyl ether to obtain {[(5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}pyridin-3-yl)carbonyl]amino}acetic acid (348 mg).

According to the amidation as in Example 244, the compounds of Examples 245 to 257 were obtained.

Example 258

Water (4 ml), sodium carbonate (337 mg) and tetrakistriphenylphosphine palladium (115 mg) were added in that order to a dimethoxyethane (12 ml) solution containing the compound (400 mg) of Example 54 and [3-(aminocarbonyl)phenyl]boronic acid (176 mg), followed by heating at 80° C. for 5 hours. The reaction solution was cooled and diluted with EtOAc. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:5 (v/v)) to obtain 5-[3-(aminocarbonyl)phenyl]pyridin-3-yl-4-benzylpiperidine-1-carboxylate (205 mg).

In the same manner as in Example 258, the compounds of Examples 259, 265, 266 and 399 were obtained.

Example 260

A 4 M hydrogen chloride/dioxane solution (1.8 ml) was added to a THF (10 ml) solution containing 5-[(tert-butoxycarbonyl)amino]pyridin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (174 mg), followed by stirring at 60° C. for 4 hours. The solvent was evaporated under reduced pressure to obtain 5-aminopiperidin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}pyridine-1-carboxylate hydrochloride (74 mg).

Example 261

An aqueous 1 M sodium hydroxide solution (3.24 ml) was added to a THF (10 ml) solution containing 5-[4-(ethoxycarbonyl)piperidin-1-yl]pyridin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate oxalate (240 mg), followed by stirring at 60° C. for 5 hours. 1 M hydrochloric acid (3.24 ml) was added to the reaction solution and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)). The resulting oil was dissolved in ethanol/water, then oxalic acid (24 mg) was added thereto for crystallization to obtain 1-(5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}pyridin-3-yl)piperidine-4-carboxylic acid oxalate (93 mg).

Example 262

TFA (1.0 ml) was added to a methylene chloride (10 ml) solution containing 5-[(2-tert-butoxy-2-oxoethoxy)methyl]pyridin-3-yl 4-{4-[(3-(3-fluorobenzyl)oxy]phenoxy}piperidin-1-carboxylate (333 mg), followed by stirring overnight at room temperature. The solvent was evaporated under reduced pressure to obtain [(5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}pyridin-3-yl}methoxy]acetic acid (232 mg).

Example 263

An aqueous 1 M sodium hydroxide solution (7.65 ml) was added to a THF (20 ml) solution containing 5-[(acetoxy)methyl]pyridin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate oxalate (1.10 g), followed by stirring at 65° C. for 3 hours. The reaction liquid was neutralized with 1 M hydrochloric acid, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=12:1 (v/v)) to obtain 5-(hydroxymethyl)piperidin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (770 mg).

Example 264

An aqueous 1 M sodium hydroxide solution (1.11 ml) was added to a THF (5 ml) solution containing 5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]pyridin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (158 mg), followed by stirring at 60° C. for 3 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain (2E)-3-(5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}pyridin-3-yl)acrylic acid (88 mg).

Example 267

(a) Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (723 mg) was added to an acetonitrile (10 ml) solution of 3-[2-(4-piperidyl)ethyl]benzonitrile hydrochloride (475 mg) and TEA (0.58 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with EtOAc, followed by washing with an aqueous saturated sodium hydrogencarbonate solution and drying over anhydrous magnesium sulfate. The solvent was evaporated, the resulting residue was subjected to basic silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) and the side-product, nitrophenol was removed. Then, this was purified by silica gel column chromatography (eluent: hexane:EtOAc=3:2 (v/v)) to obtain methyl 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (284 mg).

(b) An aqueous 1 M sodium hydroxide solution (0.69 ml) was added to a THF (5 ml)/water (4 ml) solution of methyl 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (272 mg), followed by stirring overnight at room temperature. 1 M hydrochloric acid (0.69 ml) was added to the reaction liquid, and the crystal precipitated was collected by filtration. The crystal was washed with a hot methanol/water solution, and dried to obtain 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinic acid (240 mg).

In the same manner as in the step (a) in Example 267, the compounds of Reference Examples 149 to 150, and Examples 268 to 272, 392, 396, 400, 402, 413, 419, 421 and 422 were obtained.

According to the same method containing the step (b) after the step (a) as in Example 267, the compounds of Examples 273 to 317, 393 to 395, 401, 403, 405, 406, 414 and 418 were obtained.

Example 318

1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (62 mg), 1-hydroxybenzotriazole (43 mg), ammonium chloride (43 mg) and TEA (0.038 ml) were added to a DMF (3.0 ml) solution of 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinic acid (102 mg), followed by stirring overnight at room temperature. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and the crystal precipitated was collected by filtration and dried. The resulting crystal was recrystallized from EtOAc/hexane to give 5-(aminocarbonyl)-3-pyridyl 4-[2-(3-cyanophenyl)ethyl]-1-piperidinecarboxylate (81 mg).

In the same manner, the compounds of Examples 319 to 382, 397, 398, 404, 408 to 412, 415, 420 and 423 were obtained.

Example 407

Under ice cooling, potassium tert-butoxide (2.73 g) was added to a DMF (50 ml) solution of triphenyl(pyridin-4-ylmethyl)phosphonium chloride hydrochloride (4.75 g) and tert-butyl 4-formylpiperidine-1-carboxylate (1.91 g), followed by stirring overnight at room temperature. The reaction liquid was diluted with EtOAc, washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:2 (v/v)) to obtain a white solid (2.05 g).

The resulting solid (2.04 g) was dissolved in EtOAc (30 ml), and 10% palladium-carbon (200 mg) was added thereto, followed by stirring in the presence of hydrogen at room temperature for 3 hours. The catalyst was removed by filtration, the solvent was concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=1:1 (v/v)) to obtain tert-butyl 4-[(E)-2-pyridin-4-ylvinyl]piperidine-1-carboxylate (1.70 g) as a white solid.

A 4 M hydrogen chloride/EtOAc solution (0.88 ml) and platinum oxide (100 mg) were added to an ethanol (25 ml) solution of tert-butyl 4-[(E)-2-pyridin-4-ylvinyl]piperidine-1-carboxylate (1.02 g), followed by stirring in the presence of hydrogen (3.5 atm) for 24 hours. This was purged with argon, diluted with methanol, filtered through Celite, and concentrated under reduced pressure. The solid precipitated was washed with EtOAc/hexane, and dried under reduced pressure to obtain tert-butyl 4-(2-piperidin-4-ylethyl)piperidine-1-carboxylate hydrochloride (850 mg) as a white solid.

2-(Dicyclohexylphosphino)biphenyl (71 mg) and (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one-palladium (93 mg) were added to a toluene (10 ml) suspension of tert-butyl 4-(2-piperidin-4-ylethyl)piperidine-1-carboxylate hydrochloride (1.13 g), 2-chloro-6-methylpyridine (431 mg) and sodium tert-butoxide (487 mg), followed by stirring at 120° C. for 1 hour. The reaction liquid was left cooled, then an aqueous saturated sodium carbonate solution was added thereto, followed by extraction with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl 4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidine-1-carboxylate (660 mg) as a red oil.

A 4 M hydrogen chloride/EtOAc solution (2 ml) was added to an EtOAc (10 ml) solution of tert-butyl 4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidine-1-carboxylate (650 mg), followed by stirring at room temperature for 2 days. The reaction liquid was concentrated to obtain 2-methyl-6-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pyridine dihydrochloride (644 mg) as a yellow amorphous substance.

Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (505 mg) was added to an acetonitrile (10 ml) solution of 2-methyl-6-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pyridine dihydrochloride (520 mg) and TEA (0.50 ml), followed by stirring at room temperature for 3 hours. The reaction liquid was diluted with EtOAc, washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2 (v/v)) to obtain methyl 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (424 mg).

An aqueous 1 M sodium hydroxide solution (0.45 ml) was added to a THF (5 ml) solution of methyl 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (208 mg), followed by stirring overnight at room temperature. The reaction liquid was concentrated to obtain sodium 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (158 mg).

1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (103 mg), 1-hydroxybenzotriazole (90 mg) and ammonium chloride (119 mg) were added to a DMF (10 ml) solution of sodium 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (210 mg), followed by stirring overnight at room temperature.

The reaction liquid was diluted with EtOAc, washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was recrystallized from EtOAc/hexane to obtain 5-(aminocarbonyl)pyridin-3-yl 4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidine-1-carboxylate (150 mg).

Example 438 Screening for FAAH Activity-Inhibiting Substance with Rat Brain Homogenate

(1) Preparation of Rat Brain Homogenate:

The head of a 10-week age SD-line male rat (Japan SLC) was cut off, and its cerebrum was taken out and weighed. Five times by volume its weight of an ice-cooled buffer (50 mM Tris-HCl (pH 7.4), 0.32 M sucrose) was added, and this was homogenized with a homogenizer in ice to give a uniform suspension. This was centrifuged (1500×g, 4° C., 15 minutes), and the supernatant was again centrifuged (15000×g, 4° C., 20 minutes) to obtain a precipitate. Further, using an ultrasonic wave generator (UR-20P, Tommy Seiko), this was ultrasonicated (power dial 4) for 5 seconds. The protein concentration of the resulting homogenate was measured according to a dye-coupling method (protein assay CBB solution, Nacalai Tesque). Using a buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA, 0.1 mg/ml BSA, 100 mM NaCl), the rat brain suspension was diluted so that its protein concentration could be 60 μg/ml, thereby preparing an enzyme solution.

(2) Screening for FAAH Activity-Inhibiting Substance:

A substrate solution was prepared, comprising 2 μCi/ml radiolabeled anandamide (Anandamide [ethanolamine 1-³H] (American Radiolabeled Chemical)), 8 μM anandamide (Funakoshi), 50 mM Tris-HCl (pH 8.0), 1 mM EDTA, 0.1 mg/ml BSA and 100 mM NaCl. Test substance solutions were prepared, dissolved in DMSO to have a concentration of from 1 nM to 100 μM. 50 μl of the substrate solution and 1 μm of the test substance solution were added to 50 μl of the enzyme solution, and left for 1 hour. As a control, DMSO was used in place of the test substance solution. To this, added was 200 μl of a 1:1 (by volume) solution of chloroform/methanol, followed by vortexing. This was centrifuged (15000 rpm, 2 minutes), whereby the decomposed product ethanolamine (ethanolamine 1-³H) was separated in the upper layer (water/methanol layer) and the unreacted radiolabeled anandamide (Anandamide [ethanolamine 1-³H]) was in the lower layer (chloroform layer). 30 μl of the upper layer was transferred into a 96-well organic solvent-resistant white microplate (PicoPlate-96; Perkin Elmer), 150 μl of Microscint-20 (Perkin Elmer) was added thereto, and this was measured with a microplate scintillation counter (TopCount™; Beckman). As compared with the control, the substance that gave a decreased value was selected as an FAAH activity-inhibiting substance.

(3) Measurement of IC₅₀ Value of FAAH Activity-Inhibiting Substance:

A test compound was dissolved in DMSO to have a varying concentration of from 1 nM to 100 μM to prepare test substance solutions. According to the method mentioned above, the compound was analyzed for its influence on FAAH activity. As a control, DMSO was used. A measured value of a case where a buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA, 0.1 mg/ml BSA, 100 mM NaCl) was reacted in place of the enzyme solution was subtracted from every measured value. Based on the measured value of the control, 100%, IC₅₀ value of the test substance was obtained. For example, IC₅₀ of the compounds of Examples 2, 151, 225, 228, 273, 324, 325 and 359 was 0.14 nM, 27 nM, 0.37 nM, 0.19 nM, 0.65 nM, 0.54 nM, 2.5 mM and 1.3 nM, respectively.

The above results confirm that, when a test substance is contacted with a homogenate of a tissue that expresses FAAH or functional FAAH and when the test substance-dependent FAAH activity change is measured, then it may be screened for an FAAH activity-inhibiting substance, or that is, a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain.

Example 439 Screening for FAAH Activity-Inhibiting Substance with Human Bladder Epithelial Cancer-Derived Cell

(1) Screening for FAAH Activity-Inhibiting Substance:

Human bladder epithelial cancer-derived cell line 5678 cells (HTB-9; ATCC) were seeded on a 48-well cell culture plate in an amount of 1×10⁵ cell/well, using 10% fetal bovine serum (HyClone)-containing RPMI1640 medium (Invitrogen). After incubated at 37° C. for at least 12 hours, the cells were washed with 400 μl/well of a buffer (Hank's Balanced Salt Solution, 20 mM Hepes-NaOH (pH 7.4)). A test substance dissolved in DMSO was added to a substrate solution (the above buffer containing 3 μCi/ml radiolabeled anandamide (Anandamide [ethanolamine 1-3H]) and 10 μM anandamide) so as to have a concentration of from 0.003 nM to 30 nM. As a control, DMSO alone was added. 100 μl/well of the substrate solution was added to the above cells, and incubated in a CO₂ incubator at 37° C. for 30 minutes. Next, the cell culture plate was transferred onto ice, and the substrate solution was removed by suction; and 75 μl/well of a cytolytic solution (the above buffer containing 0.5% Triton X-100, and 10 μM of FAAH-inhibitory activity-having compound, 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597; Cayman chemical; Kathuria et al., Nature Med., Vol. 9, pp. 76-81, 2003)) was added thereto, followed by stirring. The resulting cell lysate in every well was individually transferred into a 1.5 ml sample tube, to which was added 150 μl of 1:1 (by volume) chloroform/methanol solution, followed by vortexing. This was centrifuged (15000 rpm, 2 minutes), whereby the decomposed product, ethanolamine (ethanolamine 1-³H) was separated in the upper layer (water/methanol layer) and the unreacted radiolabeled anandamide was in the lower layer (chloroform layer). 25 μl of the upper layer was transferred into a 96-well organic solvent-resistant white microplate (PicoPlate-96; Perkin Elmer), 150 μl of Microscint-20 (Perkin Elmer) was added thereto, and this was measured with a microplate scintillation counter (TopCount™; Beckman). As compared with the control, the substance that gave a decreased value was selected as an FAAH activity-inhibiting substance.

(2) Measurement of IC₅₀ Value of FAAH Activity-Inhibiting Substance:

A test compound dissolved in DMSO to have a concentration of 10 mM was dissolved in the substrate solution so as to have a varying concentration of from 0.003 nM to 30 μM. According to the method mentioned above, the compound was analyzed for its influence on FAAH activity. As a negative control, DMSO was used. As a positive control, URB597 was added to the substrate solution to have a concentration of 10 μM. Based on the measured value of the positive control, 0%, and on the measured value of the negative control, 100%, IC₅₀ value of the test substance was obtained. The test results are shown in Table 64.

The above results confirm the excellent FAAH inhibitory activity of typical compounds of the present invention. In addition, these indicate that, when a test substance is contacted with a cell that expresses FAAH or functional FAAH and when the test substance-dependent FAAH activity change is measured, then it may be screened for an FAAH activity-inhibiting substance, or that is, a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain.

Example 440 Screening for FAAH Activity-Inhibiting Substance with Tissue Homogenate of Rat Administered with Test Substance

(1) Administration to Rat, and Preparation of Tissue Homogenate:

A test substance suspended in 0.5% methyl cellulose (MC) solution was orally administered to two 9-week age Wistar male rats (Japan SLC) at a dose of from 1 to 3 mg/kg. As a control, 0.5% MC solution was administered to other two rats. After 30 minutes, the blood was collected from each rat under ether anesthesia through its aorta. With that, the head of each rat was cut off, and its cerebrum was taken out.

3 ml of the collected blood was diluted with the same amount of physiological saline water, and gently put on 3 ml of a hemocyte-separating agent (Nycoplep; AXIS-SHIELD) in a centrifugal tube. This was centrifuged (400×g, 20 minutes) to collect the monocytic layer. The resulting monocytes were washed twice with physiological saline, and frozen and stored at −20° C. until their use for measurement.

To the collected rat brain, added was five times by volume its weight of an ice-cooled buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA), and this was homogenized with a homogenizer in ice to give a uniform suspension. Further, using an ultrasonic wave generator (UR-20P (power dial 4), Tommy Seiko), this was ultrasonicated for 5 seconds. To the above frozen monocytes, added was 1001 of an ice-cooled buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA), and using an ultrasonic wave generator (UR-20P (power dial 4), Tommy Seiko), this was ultrasonicated for 5 seconds. The protein concentration of each of the homogenates of brain and monocytes was measured according to a dye-coupling method (protein assay CBB solution, Nacalai Tesque). Using a buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA, 0.1 mg/ml BSA, 100 mM NaCl), the homogenates of brain and monocytes were diluted so that their protein concentration could be 80 μg/ml and 400 μg/ml thereby preparing enzyme solutions.

(2) Measurement of FAAH Activity:

50 μl of the enzyme solution was reacted with 50 μl of a substrate solution (2 μCi/ml radiolabeled anandamide (Anandamide [ethanolamine 1-³H] (American Radiolabeled Chemical)), 8 μM anandamide (Funakoshi), 50 mM Tris-HCl (pH 8.0), 1 mM EDTA) added thereto, at room temperature for 1 hour. 200 μl of a 1:1 (by volume) solution of chloroform and methanol was added to it, followed by vortexing. This was centrifuged (12000×g, 2 minutes), whereby the decomposed product ethanolamine (ethanolamine 1-³H) was separated in the upper layer (water/methanol layer) and the unreacted radiolabeled anandamide (Anandamide [ethanolamine 1-³H]) was in the lower layer (chloroform layer). 25 μl of the upper layer was transferred into a 96-well organic solvent-resistant white microplate (PicoPlate-96; Perkin Elmer), 150 μl of Microscinti-20 (Perkin Elmer) was added thereto, and this was measured with a microplate scintillation counter (TopCount™; Beckman).

Based on the FAAH activity of the control, test substance-free, rat brain or monocyte homogenate, 100%, and on the FAAH activity of the tissue homogenate-free buffer (50 mM Tris-HCl (pH 8.0), 1 mM EDTA, 0.1 mg/ml BSA, 100 mM NaCl), 0%, the relative value (%) of the FAAH activity of the tissue homogenate of the rat administered with the test substance was obtained. The substance that decreased the relative value of FAAH activity was selected as an FAAH activity-inhibiting substance.

The above results confirm that, when a test substance is administered to a test animal and when the test substance-dependent FAAH activity change in the tissue homogenate of the animal is measured, then it may be screened for an FAAH activity-inhibiting substance, or that is, a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain.

Example 441 Effect of Compound to Cyclophosphamide (CPA)-Induced Urinary Frequency in Rat

Compounds were tested for their bladder irritation-relieving effect, using pathologic models. It is known that systemic administration of cyclophosphamide (CPA) converts the compound into its metabolite, acrolein, and, as existing in urine, this injures the bladder mucosa. In rats, CPA administration induces bladder pain or urinary frequency accompanied by hemorrhagic cystitis, and therefore using such rats, it is possible to evaluate the potency of drug for these symptoms. In this experiment, used were 9-week age Wistar female rats (Charles River). CPA (100 mg/kg) was intraperitoneally administered to the rats, and after 2 days, the rats were tested. A test compound was orally administered (p.o.) to the rats; and after 15 minutes, distilled water (30 ml/kg) was forcedly orally administered thereto. The rats were put in a metabolic cage, and their urine was continuously measured for 1 hour. The overall urine amount was divided by the overall urination frequency, and the effective bladder capacity was thus calculated. As a result, in the group administered with the solvent, 0.5% methyl cellulose (MC), the effective bladder capacity reduced, and the rats showed urinary frequency. In oral administration, effective dose of compounds of Examples 2, 218 and 261 was 3 mg/kg; that of compounds of Examples 225, 228, 273, 313, 324, 325 and 359 was 1 mg/kg. These compounds increased the reduced effective bladder capacity and relieved the condition of urinary frequency.

Example 442 Anti-Allodynia Effect of Compounds for L5/L6 Spinal Nerve-Ligated Rat (Neuropathic Pain Model)

A 5 to 6-week age male SD rat was subjected to operation of ligating its left-side L5 and L6 spinal nerves with silk threads. For evaluating the analgesic effect of a test substance, employed was a von Frey hair test. Briefly, the hind paw of the animal was picked with hair, whereupon the minimum strength of the hair for limb withdrawal response was referred to as the response threshold (log gram) to the mechanical stimulation. In the preliminary test, it was confirmed that the response threshold of the operated paw of the animal remarkably lowered within 7 to 14 days after the operation (under allodynia), and the anti-allodynia effect of the test compound was evaluated on any day within 7 to 14 days after the operation. On the day before the test date, the response threshold before test compound administration was measured. The test animals were so grouped that the mean value difference and fluctuation in the threshold before test compound administration in the groups could be small. In the evaluation test of test compounds, the response threshold value after test compound administration was measured. The test compound was orally administered 60 minutes before the response threshold value measurement. Based on the response thresholds of operated and non-operated paws in the solvent-administered group, 0% and 100%, respectively, the potency of the test compound for its anti-allodynia effect was calculated. As a result, in 10 mg/kg oral administration of the compound of Example 126, it showed an anti-allodynia potency of 74%.

TABLE 1 Rex MS m/z No. Str (M + H)⁺  1

192:FAB  2

284:FAB  3

284:FAB  4

222:ESI  5

236:ESI  6

250:ESI  7

221:FAB  8

235:FAB  9

249:FAB 10

221:FAB 11

235:FAB

TABLE 2 Rex MS m/z No. Str (M + H)⁺ 12

235:FAB 13

249:FAB 14

221:FAB 15

263:FAB 16

340:FAB 17

213:FAB 18

213:FAB 19

291:FAB 20

277:FAB 21

245:FAB 22

192:FAB

TABLE 3 Rex MS m/z No. Str (M + H)⁺ 23

206:FAB 24

296:ESI 25

220:FAB 26

263:FAB 27

263:FAB 28

297:FAB 29

302:FAB 30

314:FAB 31

290:FAB 32

264:ESI 33

268:ESI

TABLE 4 Rex MS m/z No. Str (M + H)⁺ 34

302:FAB 35

309:FAB 36

304:FAB 37

303:FAB 38

305:FAB 39

298:FAB 40

248:ESI 41

318:FAB 42

318:FAB 43

350:FAB 44

332:FAB

TABLE 5 Rex MS m/z No. Str (M + H)⁺ 45

357:FAB 46

366:FAB 47

338:FAB 48

352:FAB 49

192:ESI 50

235:FAB 51

220:ESI 52

206:ESI 53

232:ESI 54

303:FAB

TABLE 6 Rex MS m/z No. Str (M + H)⁺ 55

233:ESI 56

258:ESI 57

231:FAB 58

233:FAB 59

303:FAB 60

269:FAB 61

318:FAB 62

351:ESI 63

318:FAB 64

365:FAB 65

264:FAB

TABLE 7 Rex MS m/z No. Str (M + H)⁺ 66

264:FAB 67

303:FAB 68

315:FAB 69

317:FAB 70

317:FAB 71

297:FAB 72

320:FAB 73

139:ESI 74

181:ESI

TABLE 8 Rex MS m/z No. Str (M + H)⁺ 75

196:ESI 76

251:ESI 77

140:ESI 78

209:ESI 79

182:ESI 80

240:ESI 81

180:ESI 82

168:ESI 83

369:ESI 84

370:FAB 85

383:ESI

TABLE 9 Rex MS m/z No. Str (M + H)⁺ 86

412:FAB 87

483:FAB 88

384:FAB 89

538:ESI 90

567:ESI 91

483:ESI 92

493:ESI 93

522:ESI 94

251:ESI

TABLE 10 MS m/z (M + H)⁺ or Rex (M − H)⁻ or (M)⁺ No. Str FAB or ESI or EI  95

215(M + H)⁺ FAB  96

268, 270(M + H)⁺ FAB  97

208(M + H)⁺ FAB  98

220(M + H)⁺ FAB  99

224(M + H)⁺ FAB 100

215(M + H)⁺ FAB 101

215(M + H)⁺ FAB 102

348(M + H)⁺ FAB 103

348(M + H)⁺ ESI 104

332(M − H)⁻ ESI 105

332(M − H)⁻ ESI 106

333(M + H)⁺ ESI

TABLE 11 MS m/z (M + H)⁺ or Rex (M − H)⁻ or (M)⁺ No. Str FAB or ESI or EI 107

375(M + H)⁺ ESI 108

389(M + H)⁺ ESI 109

377(M − H)⁻ API 110

375(M − H)⁻ API 111

361(M + H)⁺ ESI 112

387(M + H)⁺ FAB 113

401(M + H)⁺ FAB 114

377(M + H)⁺ ESI 115

389(M + H)⁺ ESI 116

387(M + H)⁺ ESI 117

478(M + H)⁺ ESI 118

479(M + H)⁺ FAB

TABLE 12 MS m/z (M + H)⁺ or Rex (M − H)⁻ or (M)⁺ No. Str FAB or ESI or EI 119

359(M + H)⁺ ESI 120

233(M + H)⁺ FAB 121

247(M + H)⁺ FAB 122

275(M + H)⁺ ESI 123

289(M + H)⁺ ESI 124

315(M + H)⁺ FAB 125

279(M + H)⁺ ESI 126

277(M + H)⁺ ESI 127

261(M + H)⁺ FAB 128

287(M + H)⁺ ESI 129

301(M + H)⁺ ESI 130

303(M + H)⁺ ESI

TABLE 13 MS m/z (M + H)⁺ or Rex (M − H)⁻ or (M)⁺ No. Str FAB or ESI or EI 131

378(M + H)⁺ ESI 132

379(M + H)⁺ ESI 133

233(M + H)⁺ ESI 134

260(M)⁺ ESI 135

288(M + H)⁺ ESI 136

259(M + H)⁺ ESI 137

286(M + H)⁺ ESI 138

378(M + H)⁺ ESI 139

379(M + H)⁺ ESI 140

266(M + H)⁺ FAB 141

291(M + H)⁺ FAB 142

267(M + H)⁺ FAB 143

302(M + H)⁺ FAB

TABLE 14 MS m/z (M + H)⁺ or (M − H)⁻ Rex or (M)⁺ No. Str FAB or ESI or EI 144

338 (M + H)⁺ ESI 145

338 (M + H)⁺ FAB 146

339 (M + H)⁺ ESI 147

341 (M + Na)⁺ ESI 148

261 (M + H)⁺ ESI 149

466 (M + H)⁺ FAB 150

480 (M + H)⁺ ESI 151

438 (M + H)⁺ ESI 152

427 (M + H)⁺ ESI 153

481 (M + H)⁺ FAB

TABLE 15 MS m/z (M + H)⁺ or (M − H)⁻ Rex or (M)⁺ No. Str FAB or ESI or EI 154

338 (M + H)⁺ ESI 155

186 (M + H)⁺ ESI

TABLE 16

Ex No. T R¹ R² R⁴ Sal 001 CH H H H oxal 002 CH 4-(3-FPhCH₂O)PhO H H free 003 CH 4-(3-FPhCH₂O)PhCO H H free 004 N 4-(3-FPhCH₂O)PhCO H H oxal 005 N 4-cHexCH₂OPhCO H H free 006 N 4-cHex(CH₂)₂OPhCO H H free 007 N 4-cHepCH₂OPhCO H H free 008 N 4-PhCH₂OPhCO H H free 009 CH 4-cHexCH₂OPhO H H free 010 CH PhCH₂ H H oxal 011 CH 3-PhCH₂OPhO H H free 012 CH 4-PhCH₂OPhO H H free 013 CH 4-(3-FPhCH₂O)PhO H 6′-Me HCl 014 CH PhCO H H free 015 CH 4-FPh H H free 016 CH PhCONH H H free 017 N Ph(CH₂)₂ H H free 018 CH

H H HCl 019 CH

H H free 020 CH

H H HCl 021 CH PhO H H HCl 023 N Ph H H free 024 CH 4-H₂NCOPhO H H free

TABLE 17

Ex No. T R¹ R² R⁴ Sal 025 CH 4-H₂NCOCH₂PhO H H free 026 CH 4-H₂NCO(CH₂)₂PhO H H free 027 CH 3-H₂NCOPhO H H oxal 028 CH 3-H₂NCOCH₂PhO H H oxal 029 CH 4-(3-FPhCH₂O)PhO H 5′-COOMe free 030 CH 4-(3-FPhCH₂O)PhO H 5′-NMe₂ HCl 031 CH 4-cHexCH₂N(Me)PhO H H 2HCl 033 N Ph(CH₂)₅ H H 2HCl 034 N 4-PhCH₂OPh H H free 035 CH Ph(CH₂)₂ H H HCl 036 CH PhCH₂O H H HCl 037 C Ph 4-HO H HCl 039 C Ph 4-Ac H free 040 CH Ph H H HCl 041 CH 4-H₂NCOPhOCH₂ H H free 042 CH 4-(3-FPhCH₂O)PhO H 5′-Cl free 043 CH 4-H₂NCOPhO(CH₂)₂ H H free 044 CH 4-(3-FPhCH₂O)PhO H 5′-Br free 045 CH 4-(3-FPhCH₂O)PhO H 5′-Mo4 HCl 046 CH 4-H₂NCOPhCH₂O H H free 047 CH PhCH₂NHCO H H free 048 N 3-PhCH₂OPh H H 2HCl 049 N Ph(CH₂)₄ H H free 050 N tBuOCO H H free 051 CH 2-Cl-4-PhCH₂OPhO H H HCl 052 CH PhCH₂ H 6′-Me HCl 053 CH PhCH₂O(CH₂)₂ H H HCl 054 CH PhCH₂ H 5′-Br free 055 CH PhCH₂ H 6′-CH₂OMe free 056 CH 4-(3-FPhCH₂O)PhO H 5′-N(Me)(CH₂)₂NMe₂ 2HCl 057 CH 2-H₂NCOPhO H H oxal 058 N 4-(3-FPhCH₂O)PhSO₂ H H free 059 CH Ph₂(HO)C H H HCl 060 CH 3-HOPh H H free 061 CH 4-(3-FPhCH₂O)PhO H 5′-(CH₂)₂COOMe free 062 N Ph(CH₂)₂OCO H H free 063 CH 4-H₂NCOPh(CH₂)₂ H H free 064 CH PhCH₂NHCOCH₂ H H HCl

TABLE 18

Ex No. T R¹ R² R⁴ Sal 066 CH 1-MeBenzIM2(CH₂)₃ H H free 067 C Ph 4-NC H HCl 068 CH 2-oxoBenzIM 1 H H free 069 CH 4-H₂NCOPhO(CH₂)₃ H H free 070 CH 3-Cl-4-PhCH₂OPhO H H oxal 071 CH 4-[3-FPhSO₂N(Me)]PhO H H HCl 072 N PhCH₂OCO 3- H HCl H₂NCO 073 CH 4-(3-FPhCH₂O)PhO H 5′- oxal (4-EtOCOPIPE1)- 074 C PhCH₂ 4-HO H HCl 075 N 4-BuNHCOCH₂OPhCO H H p-tol 076 CH 4-(3-FPhCH₂O)PhS H H p-tol 077 CH 3-EtOCOCH₂OPh H H oxal 078 CH 3-PhCH₂OPh H H oxal 079 CH 4-PhCH₂OCOPhO(CH₂)₂ H H free 080 CH 4-(3-FPhCH₂O)PhSO₂ H H free 081 CH PhCH₂OCH₂ H H oxal 082 CH 4-PhCH₂OPhO H 5′-COOMe free 083 CH 3-(3-H₂NCOPh)PhO H H HCl 084 N Ph(CH₂)₂ 3-oxo H free 085 N Ph(CH₂)₂ H 5′-Cl free 086 N Ph(CH₂)₂ H 5′-COOMe free 087 CH 6-ClPy3O H H free 088 CH 4-PhCH₂OPhSO₂ H H free 089 CH 4-(3-NCPhCH₂O)PhSO₂ H H free 090 CH 4-cHexCH₂OPhSO₂ H H free 091 CH 4-cHex(CH₂)₂OPhSO₂ H H free 092 CH 6-ClPy2O H H HCl 093 CH 6-(3-FPhCH₂O)Py2O H H oxal 094 CH 6-(3-H₂NCOPh)Py2O H H free 095 CH 4-(3-ClPhCH₂O)PhSO₂ H H free 096 N 4-H₂NCOPhCH₂OCO H H free 097 CH 4-(3-FPhCH₂O)PhO H 5′-Me free 098 CH 4-Me₂NCOPhO(CH₂)₃ H H p-tol 099 CH 4-MeNHCOPhO(CH₂)₃ H H free 100 CH 4-(3-FPhCH₂O)PhO H 5′-CH₂OAc oxal 101 CH 3-(3-FPhCH₂O)PhS H H p-tol

TABLE 19

Ex No. T R¹ R² R⁴ Sal 102 CH 6-[cHex(CH₂)₂O]Py2O H H oxal 103 CH 5-(3-FPhCH₂O)Py2O H H oxal 105 CH 3-(3-FPhCH₂O)PhSO₂ H H free 106 CH 4-NCPhO(CH₂)₃ H 5′-COOMe free 107 CH H 3-PhOCH₂ H p-tol 108 CH 4-NCPhO(CH₂)₃ H H free 109 CH HO H H free 110 CH PhOCH₂ H H free 111 CH PhO(CH₂)₂ H H p-tol 112 CH Ph(CH₂)₃O(CH₂)₂ H H oxal 113 CH 3-Ph(CH₂)₃OPh H H oxal 114 CH PhO(CH₂)₃ H H free 115 CH 2-H₂NCOPhO(CH₂)₃ H H free 116 CH 3-H₂NCOPhO(CH₂)₃ H H p-tol 118 CH 4-(3-FPhCH₂O)PhO H 5′-F HCl 119 N 4-cOctCH₂OPhCO H H free 120 N 4-[3-FPhCH₂N(Me)]PhCO H H free 121 N 4-cHexCH₂N(Me)PhCO H H free 122 N 3-cHexCH₂OPhCO H H HCl 123 N 3-cHexCH₂N(Me)PhCO H H HBr 124 N Ph(CH₂)₂CO H H p-tol 125 N PhCO H H free 127 N PhOCH₂CO H H p-tol 128 N PhCH₂CO H H p-tol 129 N PhNHCH₂CO H H free 130 N Ph(CH₂)₃CO H H p-tol 132 N PhCONHCH₂CO H H oxal 133 N PhN(Me)CH₂CO H H 2oxal 134 N 4-HepOPhCO H H p-tol 135 N 4-(3-NCPhCH₂O)PhCO 2-Me H HCl 136 N 4-(3-NCPhCH₂O)PhCO 3-Me H free 137 N 6-(3-ClPhCH₂O)Py3CO H H oxal 138 N 3-(3-ClPhCH₂O)PhCO H H HCl 139 N 4-H₂NCOPhOCH₂CO H H free 140 N 2-H₂NCOPhOCH₂CO H H free 141 N 3-H₂NCOPhOCH₂CO H H free 142 N PhSO₂ H H free

TABLE 20

Ex No. T R¹ R² R⁴ Sal 143 N PhCH₂SO₂ H H free 144 N PhCH₂O—CO H H p-tol 145 N Py3O—CO H H free 146 N PhCH₂NHCO H H free 147 N 4-(3-ClPhCH₂O)PhCO H H free 148 N 4-(3-MePhCH₂O)PhCO H H oxal 149 N 4-(3-F₃CPhCH₂O)PhCO H H free 150 N 4-(3-MeOPhCH₂O)PhCO H H oxal 151 N 4-(3-NCPhCH₂O)PhCO H H free 152 N 4-(3,5-diFPhCH₂O)PhCO H H free 153 N 4-(3-F₃COPhCH₂O)PhCO H H free 154 N 4-(3-O₂NPhCH₂O)PhCO H H free 155 N 4-(4-FPhCH₂O)PhCO H H free 156 N 4-(2-FPhCH₂O)PhCO H H free 157 N 4-Py2CH₂OPhCO H H free 158 N 4-(1-MeAzep3O)PhCO H H free 159 N 4-(3-BrPhCH₂O)PhCO H H free 160 N 4-[3-ClPh(CH₂)₂O]PhCO H H free 161 N 4-(4-NCPhCH₂O)PhCO H H free 162 N 4-(3-IPhCH₂O)PhCO H H free 163 N 4-(3-Me₂NPhCH₂O)PhCO H H free 164 N 2-Cl-4-(3-NCPhCH₂O)PhCO H H free 165 N 3-Cl-4-(3-NCPhCH₂O)PhCO H H free 166 N 4-(3-NCPhCH₂O)-3-MeO-PhCO H H HCl 167 N 4-(3-MeOCOPhCH₂O)PhCO H H free 168 CH cHexCH₂NHCO H H free 169 CH MeOCO(CH₂)₃ H H oxal 170 CH H₂NCO(CH₂)₃ H H oxal 171 CH PhCH₂N(Me)CO H H free 172 CH Py3CH₂NHCO H H free 173 CH PhNHCO H H free 174 CH Ph(CH₂)₂NHCO H H free 175 CH Ph(CH₂)₄NHCO H H free 176 CH 4-OctPhNHCO H H free 177 CH 4-H₂NCOPhNHCO(CH₂)₃ H H free 178 CH 3-H₂NCOPhNHCO(CH₂)₃ H H free 179 CH 3-H₂NCOCH₂OPh H H HCl

TABLE 21

Ex No. T R¹ R² R⁴ Sal 180 CH 3-(4-H₂NCOPIPE1COCH₂O)Ph H H HCl 181 CH 2-H₂NCOPhNHCO(CH₂)₃ H H fum 182 CH 4-BuPhNHCO H H free 183 CH 4-BuOPhNHCO H H free 184 CH 4-HexOPh(CH₂)₂NHCO H H free 185 CH 4-Ph(CH₂)₄OPh(CH₂)₂NHCO H H free 186 CH 4-cPen(CH₂)₃OPh(CH₂)₂NHCO H H free 187 CH 4-HexPhNHCO H H free 188 CH 4- H H free [4-MeOCOPh(CH₂)₂]PhNHCO 189 CH 4-HO(CH₂)₂PhNHCO H H free 190 CH 4-PhCH₂OPhNHCO H H free 191 CH 2-H₂NCO(CH₂)₂PhNHCO H H free 192 CH 4-Ph-1,3-Thiaz2NHCO H H free 193 N PhCH₂OCO 3- H free COOH 194 CH 4-HOOCPhO(CH₂)₂ H H free 195 CH 3-HOOCCH₂OPh H H free 196 CH 1-MeBenzIM2 H H free 197 CH Ph(CH₂)₅CONH H H free 198 CH 3-HOPhO H H free 199 CH 4-HOPhO H H free 200 CH 3-cHexCH₂OPhO H H HCl 201 CH 3-cHex(CH₂)₂OPhO H H HCl 202 CH 3-(3-FPhCH₂O)PhO H H HCl 203 CH 3-(2-FPhCH₂O)PhO H H HCl 204 CH 3-(4-FPhCH₂O)PhO H H HCl 205 CH 3-(3-NCPhCH₂O)PhO H H oxal 206 CH 4-(3-ClPhCH₂O)PhO H H HCl 207 CH 4-cHex(CH₂)₂OPhO H H HCl 208 CH 4-(2-FPhCH₂O)PhO H H HCl 209 CH 4-(4-FPhCH₂O)PhO H H HCl 210 CH 4-(3-NCPhCH₂O)PhO H H oxal 211 CH 4-(3-MeOCOPhCH₂O)PhO H H free 212 CH 4-(3-H₂NCOPhCH₂O)PhO H H free 213 CH 4-cHex(CH₂)₃OPhO H 5′- free COOMe

TABLE 22

Ex No. T R¹ R² R⁴ Sal 214 CH 4-PIPE1(CH₂)₂OPhO H 5′-COOMe HCl 215 CH 4-(3-NCPhCH₂O)PhO H 5′-COOMe oxal 216 CH 4-cHexCH₂OPhO H 5′-COOMe free 217 CH 4-HOPhO H 5′-COOH free 218 CH 4-(3-FPhCH₂O)PhO H 5′-COOH free 219 CH PhCH₂ H 5′-COOH free 220 CH Ph H 5′-COOH free 221 CH 4-PhCH₂OPhO H 5′-COOH free 223 CH PhCO H 5′-COOH free 224 CH PhCH₂O H 5′-COOH free 225 CH Ph(CH₂)₂ H 5′-COOH free 226 CH 4-PIPERI1(CH₂)₂OPhO H 5′-COOH free 227 CH 4-NCPhO(CH₂)₃ H 5′-COOH free 228 CH 4-cHex(CH₂)₂OPhO H 5′-COOH free 229 CH 4-cHex(CH₂)₃OPhO H 5′-COOH free 230 CH 4-(3-NCPhCH₂O)PhO H 5′-COOH free 231 N Ph(CH₂)₂ H 5′-COOH 2HCl 232 CH PhCH₂OCH₂ H 5′-COOH free 233 CH 4-(3-MeOPhCH₂O)PhO H 5′-COOH free 234 CH 3-(3-FPhCH₂O)PhO H 5′-COOH free 235 CH 3-(3-NCPhCH₂O)PhO H 5′-COOH free 236 CH 4-(3-MeOCOPhCH₂O)PhO H 5′-COOH free 237 CH 4-cHexCH₂OPhO H 5′-COOH free 238 CH Ph(CH₂)₃ H 5′-COOH free 239 CH PhO(CH₂)₃ H 5′-COOH free 240 CH PhO(CH₂)₂ H 5′-COOH free 241 CH 4-H₂NCOPh(CH₂)₂ H 5′-COOH free 242 CH 3-cHex(CH₂)₂OPhO H 5′-COOH free 243 N Ph(CH₂)₃ H 5′-COONa free 244 CH 4-(3-FPhCH₂O)PhO H 5′-CONHCH₂COOH free 245 CH 4-(3-FPhCH₂O)PhO H 5-CONH₂ free 246 CH 4-PhCH₂OPhO H 5-CONH₂ free 247 CH PhCH₂ H 5′-CONHCH₂CONH₂ HCl 248 CH PhCH₂ H 5′-(4-H₂NCOPIPERI1CO)— HCl

TABLE 23

Ex No. T R¹ R² R⁴ Sal 249 CH 4-(3-FPhCH₂O)PhO H 5′-CONHCH₂CONH₂ HCl 250 CH 4-(3-FPhCH₂O)PhO H 5′-Mo4(CH₂)₂NHCO— oxal 251 CH 4-(3-FPhCH₂O)PhO H 5′-CONH(CH₂)₂OMe oxal 252 CH 4-(3-FPhCH₂O)PhO H 5-(4-H₂NCOPIPE1CO)— free 253 CH 4-(3-FPhCH₂O)PhO H 5′-CONH(CH₂)₂CONH₂ HCl 254 CH 4-(3-FPhCH₂O)PhO H 5′-PIPE1(CH₂)₂NHCO— 2HCl 255 CH 4-(3-FPhCH₂O)PhO H 5′-CONH(CH₂)₂OH HCl 256 CH 4-(3-FPhCH₂O)PhO H 5′- free (4-HOPh(CH₂)₂NHCO)— 257 CH 4-(3-FPhCH₂O)PhO H 5′-(4-MePIPERA1CO)— oxal 258 CH PhCH₂ H 5′-(3-H₂NCOPh)- free 259 CH PhCH₂ H 5′-Py3 free 260 CH 4-(3-FPhCH₂O)PhO H 5′-NH₂ HCl 261 CH 4-(3-FPhCH₂O)PhO H 5′-(4-HOOCPIPE1)- oxal 262 CH 4-(3-FPhCH₂O)PhO H 5′-CH₂OCH₂COOH free 263 CH 4-(3-FPhCH₂O)PhO H 5-CH₂OH free

TABLE 24 Ex No. Str Sal 022

free 032

2HCl 038

free 065

free 104

fum 117

free 126

p-tol 131

p-tol 222

free 264

free

TABLE 25

Ex No. T R¹ R⁴ Sal 265 CH Ph(CH₂)₂ 5′-(4-MeOCOPh)- free 266 CH Ph(CH₂)₂ 5′-(3-H₂NCOPh)- free 267 CH 3-NCPh(CH₂)₂ 5′-COOH free 268 CH

H free 269 CH

H free 270 CH Ph(CH₂)₂ 5′-Br free 271 CH cHex(CH₂)₂ H free 272 CH cHex(CH₂)₂ 5′-COOMe free 273 CH

5′-COOH free 274 CH 3-ClPh(CH₂)₂ 5′-COOH free 275 CH 4-NCPh(CH₂)₂ 5′-COOH free 276 CH 3-MeOPh(CH₂)₂ 5′-COOH free 277 CH 3-FPh(CH₂)₂ 5′-COOH free 278 CH 2-NCPh(CH₂)₂ 5′-COOH free 279 CH 3-H₂NCOPh(CH₂)₂ 5′-COOH free 280 CH 3-Me₂NCOPh(CH₂)₂ 5′-COOH free 281 CH BIP4(CH₂)₂ 5′-COOH Na 282 CH 4-FPh(CH₂)₂ 5′-COOH free 283 CH 2-ClPh(CH₂)₂ 5′-COOH free 284 CH 4-ClPh(CH₂)₂ 5′-COOH free 285 CH 4-BrPh(CH₂)₂ 5′-COOH free

TABLE 26

Ex No. T R¹ R⁴ Sal 286 CH 4-MeOPh(CH₂)₂ 5′-COOH free 287 CH Ph(CH₂)₄ 5′-COOH free 288 CH 2-FPh(CH₂)₂ 5′-COOH free 289 CH cHex(CH₂)₂ 5′-COOH free 290 CH 4-Py2Ph(CH₂)₂ 5′-COOH free 291 CH Ph(CH₂)₂

free 292 CH 3-BrPh(CH₂)₂ 5′-COOH free 293 CH BIP3(CH₂)₂ 5′-COOH free 294 CH 3′-NCBIP3(CH₂)₂ 5′-COOH free 295 CH Py4Ph(CH₂)₂ 5′-COOH free 296 CH Py3Ph(CH₂)₂ 5′-COOH free 297 CH Py2(CH₂)₂ 5′-COOH free 298 CH 3-Py2Ph(CH₂)₂ 5′-COOH Na 299 CH 4′-FBIP4(CH₂)₂ 5′-COOH free 300 CH 4′-MeOBIP4(CH₂)₂ 5′-COOH free 301 CH 4′-NCBIP4(CH₂)₂ 5′-COOH free 302 CH 3′-FBIP4(CH₂)₂ 5′-COOH free 303 CH 3′-MeOBIP4(CH₂)₂ 5′-COOH free 304 CH 2′-FBIP4(CH₂)₂ 5′-COOH free 305 CH 3-cHexNHCOPh(CH₂)₂ 5′-COOH Na 306 CH 3-PIPE1COPh(CH₂)₂ 5′-COOH Na 307 CH 3-Mo4COPh(CH₂)₂ 5′-COOH Na 308 CH 4-PIPE1COPh(CH₂)₂ 5′-COOH Na 309 CH 4-Mo4COPh(CH₂)₂ 5′-COOH Na 310 CH 3-PYRR1COPh(CH₂)₂ 5′-COOH Na 311 CH 3-(4- 5′-COOH free Py2PIPERA1CO)Ph(CH₂)₂

TABLE 27

Ex No. T R¹ R⁴ Sal 312 CH 4-Et₂NCOPh(CH₂)₂ 5′-COOH free 313 CH 1-(6-MePy2)PIPE4(CH₂)₃ 5′-COOH Na 314 CH 1-ISOQUI1PIPE4(CH₂)₃ 5′-COOH Na 315 CH 1-QUI2PIPE4(CH₂)₃ 5′-COOH Na 316 CH 4- 5′-COOH Na ISOQUI1PIPERA1(CH₂)₃ 317 CH 1-NAPH1PIPE4(CH₂)₃ 5′-COOH Na 318 CH 3-NCPh(CH₂)₂ 5-CONH₂ free 319 CH Ph(CH₂)₂ 5′-CONH(CH₂)₂OH oxal 320 CH Ph(CH₂)₂ 5′-CONH₂ free 321 CH 3-MeOPh(CH₂)₂ 5′-CONH₂ free 322 CH 3-FPh(CH₂)₂ 5′-CONH₂ free 323 CH 2-NCPh(CH₂)₂ 5′-CONH₂ free 324 CH 3-H₂NCOPh(CH₂)₂ 5′-CONH₂ free 325 CH 3-Me₂NCOPh(CH₂)₂ 5′-CONH₂ free 326 CH cHex(CH₂)₂ 5′-CONH₂ free 327 CH 3-ClPh(CH₂)₂ 5′-CONH(CH₂)₂OH oxal 328 CH 3-MeOPh(CH₂)₂ 5′-CONH(CH₂)₂OH oxal 329 CH 3-FPh(CH₂)₂ 5′-CONH(CH₂)₂OH oxal 330 CH 3-NCPh(CH₂)₂ 5′-CONH(CH₂)₂OH oxal 331 CH 2-NCPh(CH₂)₂ 5′-CONH(CH₂)₂OH oxal 332 CH Ph(CH₂)₂ 5′-CONH(CH₂)₂SO₃H HCl 333 CH Ph(CH₂)₂ 5′-CONH(CH₂)₂CONH₂ free 334 CH 2-FPh(CH₂)₂ 5′-CONH₂ free 335 CH Ph(CH₂)₂

free 336 CH Py4(CH₂)₂ 5′-CONH₂ free

TABLE 28

Ex No. T R¹ R⁴ Sal 337 CH Py3(CH₂)₂ 5′-CONH₂ free 338 CH 4′-FBIP4(CH₂)₂ 5′-CONH₂ free 339 CH 4′-MeOBIP4(CH₂)₂ 5′-CONH₂ free 340 CH BIP3(CH₂)₂ 5′-CONH₂ free 341 CH 3′-NCBIP3(CH₂)₂ 5′-CONH₂ free 342 CH Ph(CH₂)₂ 5′-CONH(CH₂)₃OH oxal 343 CH Ph(CH₂)₂ 5′-CONH(CH₂)₃NMe₂ oxal 344 CH 4′-NCBIP4(CH₂)₂ 5′-CONH₂ free 345 CH 3′-FBIP4(CH₂)₂ 5′-CONH₂ free 346 CH 2′-FBIP4(CH₂)₂ 5′-CONH₂ free 347 CH Ph(CH₂)₂ 5′-CONH(CH₂)₂Py4 oxal 348 CH Ph(CH₂)₂ 5′-CONH(CH₂)₂Py3 oxal 349 CH 3-Py2Ph(CH₂)₂ 5′-CONH₂ free 350 CH 2-Me₂NCOPh(CH₂)₂ 5′-CONH₂ free 351 CH 3-cHexNHCOPh(CH₂)₂ 5′-CONH₂ free 352 CH 3-MeNHCOPh(CH₂)₂ 5′-CONH₂ free 353 CH 4-H₂NCOPh(CH₂)₂ 5′-CONH₂ free 354 CH 4-Me₂NCOPh(CH₂)₂ 5′-CONH₂ free 355 CH 3-PIPE1COPh(CH₂)₂ 5′-CONH₂ free 356 CH 3-Mo4COPh(CH₂)₂ 5′-CONH₂ free 357 CH 4-PIPE1COPh(CH₂)₂ 5′-CONH₂ free 358 CH 4-Mo4COPh(CH₂)₂ 5′-CONH₂ free 359 CH 3-PYRR1COPh(CH₂)₂ 5′-CONH₂ free 360 CH 3-Et₂NCOPh(CH₂)₂ 5′-CONH₂ free 361 CH

5′-CONH₂ free

TABLE 29

Ex No. T R¹ R⁴ Sal 362 CH 4-Et₂NCOPh(CH₂)₂ 5′-CONH₂ free 363 CH 4-PYRR1COPh(CH₂)₂ 5′-CONH₂ free 364 CH

5′-CONH₂ free 365 CH 3-(4-Py2PIPERA1CO)Ph(CH₂)₂ 5′-CONH₂ free 366 CH 3-(4-PhPIPERA1CO)Ph(CH₂)₂ 5′-CONH₂ free 367 CH 4-(4-Py2PIPERA1CO)Ph(CH₂)₂ 5′-CONH₂ free 368 CH 4-(4-PhPIPERA1CO)Ph(CH₂)₂ 5′-CONH₂ free 369 CH 3-FCH₂CH₂NHCOPh(CH₂)₂ 5′-CONH₂ HCl 370 CH 3-HO(CH₂)₂NHCOPh(CH₂)₂ 5′-CONH₂ free 371 CH 3-tBuNHCOPh(CH₂)₂ 5′-CONH₂ free 372 CH 3-iPrNHCOPh(CH₂)₂ 5′-CONH₂ free 373 CH 4-(2,2-DIFPYRR1CO)Ph(CH₂)₂ 5′-CONH₂ free 374 CH 3-H₂NCONHPh(CH₂)₂ 5′-CONH₂ free 375 CH 3-PYRR1CONHPh(CH₂)₂ 5′-CONH₂ free 376 CH 3-(2,2-DIFPYRR1CO)Ph(CH₂)₂ 5′-CONH₂ free 377 CH 3-(4-NAPH1PIPERA1CO)Ph(CH₂)₂ 5′-CONH₂ free 378 CH 1-(6-MePy2)PIPE4(CH₂)₃ 5′-CONH₂ free 379 CH 1-ISOQUI1PIPE4(CH₂)₃ 5′-CONH₂ free 380 CH 1-QUI2PIPE4(CH₂)₃ 5′-CONH₂ free 381 CH 4-ISOQUI1PIPERA1(CH₂)₃ 5′-CONH₂ free 382 CH 1-NAPH1PIPE4(CH₂)₃ 5′-CONH₂ free

TABLE 30

Ex No. R¹ R⁴ Sal 383 3-HepOPhNHCO H free 384 4-HepOPhNHCO H free 385 Py2NHCO(CH₂)₃ H 2HCl 386 4-OctPhNHCO(CH₂)₃ H oxal 387 Ph(CH₂)₄NHCO(CH₂)₃ H oxal 388 4-HexPhNHCO CONH₂ free 389 4-(3-FPhCH₂O)PhO OAc oxal 390 4-(3-FPhCH₂O)PhO OH free 391 4-(3-FPhCH₂O)PhO CN free 392 4-cHex(CH₂)₄OPhO H free 393

CO₂H free 394

CO₂H free 395 4-cPen(CH₂)₂OPhO CO₂H free 396 4-(3-FPhCH₂O)PhOCH₂ H free

TABLE 31

Ex No. R¹ R⁴ Sal 397

CONH₂ free 398

CONH₂ free 399 Ph(CH₂)₂

free 400 4-(3-FPhCH₂O)PhCH₂ H HCl 401 4-(3-FPhCH₂O)PhCH₂ CO₂H free 402 Ph(CH₂)₂ OH free 403

CO₂H free 404

CONH₂ free 405 4-NAPH1PIPERA1(CH₂)₃ CO₂H Na 406 1-(6-MePy2)PIPE4(CH₂)₂ CO₂H Na 407 1-(6-MePy2)PIPE4(CH₂)₂ CONH₂ free 408 4-NAPH1PIPERA1(CH₂)₃ CONH₂ free

TABLE 32

Ex No. R¹ R⁴ Sal 409 Ph(CH₂)₃ CONH₂ free 410 Ph CONH₂ free 411 Ph(CH₂)₅ CONH(CH₂)₂OH 2HCl 412 Ph(CH₂)₅ CONH₂ free 413 4-(3-FPhCH₂O)PhCH₂ H 2HCl 414 BIP4(CH₂)₂ CO₂H Na 415 BIP4(CH₂)₂ CONH₂ free

TABLE 33 Ex No. Str Sal 416

p-tol 417

free 418

free 419

p-tol 420

oxal 421

free 422

HCl 423

free

TABLE 34

Ex No. T R¹ Sal 424 CH Ph(CH₂)₂ free 425 N Ph(CH₂)₂ free 426 CH Ph(CH₂)₃ free 427 CH 4-H₂NCOPh(CH₂)₂ free 428 CH 3-cHex(CH₂)₂OPhO free 429 N Ph(CH₂)₃ free 430 CH 4-cHex(CH₂)₂OPhO free 431 CH 4-(3-MeOPhCH₂O)PhO free 432 CH 4-(3-MeOCOPhO)PhO free 433 CH 3-PYRR1COPh(CH₂)₂ free 434 CH 3-PIPE1COPh(CH₂)₂ free 435 CH

free 436 CH 3-H₂NCONHPh(CH₂)₂ free 437 CH 3-PIPE1CONHPh(CH₂)₂ free

TABLE 35 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 001 207 (M + H)⁺FAB 002 1.59-1.74 (2H, br), 1.90-2.05 (2H, br), 3.33-3.45 (1H, br), 3.45-3.55 (1H, br), 3.65-3.79 (1H, br), 3.84-3.94 (1H, br), 4.45-4.55 (1H, m), 5.07 (2H, s), 6.97 (4H, s), 7.15 (1H, dt, J = 2.4, 8.1 Hz), 7.24-7.30 (2H, m), 7.40-7.47 (2H, m), 7.64-7.66 (1H, m), 8.41-8.45 (2H, m), DMSO: 423 (M + H)⁺FAB 003 1.40-1.70 (2H, m), 1.85 (2H, d, J = 12.7 Hz), 3.10 (1H, t, J = 12.7 Hz) 3.25 (1H, t, J = 12.2 Hz), 3.65-3.75 (1H, m), 4.06 (1H, d, J = 12.2 Hz), 4.23 (1H, d, J = 12.7 Hz), 5.26 (2H, s), 7.14-7.22 (3H, m), 7.29-7.34 (2H, m), 7.42-7.50 (2H, m), 7.64-7.67 (1H, m), 8.03 (2H, d, J = 9.3 Hz), 8.44-8.45 (2H, m), DMSO: 435 (M + H)⁺FAB 004 436 (M + H)⁺FAB 005 424 (M + H)⁺FAB 006 438 (M + H)⁺FAB 007 438 (M + H)⁺FAB 008 418 (M + H)⁺FAB 009 411 (M + H)⁺FAB 010 1.10-1.30 (2H, br), 1.64 (2H, d, J = 12.7 Hz), 1.71-1.82 (1H, m), 2.56 (2H, d, J = 7.4 Hz), 2.83 (1H, t, J = 11.8 Hz), 2.99 (1H, t, J = 11.8 Hz), 4.00 (1H, d, J = 11.8 Hz), 4.15 (1H, d, J = 11.8 Hz), 7.16-7.23 (3H, m), 7.26-7.32 (2H, m), 7.44 (1H, dd, J = 4.4, 8.3 Hz), 7.59-7.64 (1H, m), 8.40 (1H, d, J = 2.0 Hz), 8.43 (1H, d, J = 4.4 Hz), DMSO: 297 (M + H)⁺FAB 011 1.59-1.75 (2H, br), 1.90-2.06 (2H, br), 3.33-3.43 (1H, br), 3.45-3.55 (1H, br), 3.65-3.79 (1H, br), 3.83-3.94 (1H, br), 4.60-4.69 (1H, m), 5.09 (2H, s), 6.57-6.66 (3H, m), 7.19 (1H, t, J = 8.3 Hz), 7.30-7.47 (6H, m), 7.62-7.66 (1H, m), 8.41-8.45 (2H, m), DMSO: 405 (M + H)⁺FAB 012 1.59-1.74 (2H, br), 1.90-2.05 (2H, br), 3.33-3.43 (1H, br), 3.45-3.55 (1H, br), 3.65-3.79 (1H, br), 3.84-3.94 (1H, br), 4.47-4.55 (1H, m), 5.04 (2H, s), 6.95 (4H, s), 7.30-7.46 (6H, m), 7.61-7.66 (1H, m), 8.41-8.45 (2H, m), DMSO: 405 (M + H)⁺FAB 013 1.59-1.76 (2H, br), 1.90-2.05 (2H, br), 2.69 (3H, s), 3.33-3.45 (1H, br), 3.45-3.60 (1H, br), 3.65-3.79 (1H, br), 3.84-3.94 (1H, br), 4.48-4.57 (1H, m), 5.07 (2H, s), 6.97 (4H, s), 7.15 (1H, dt, J = 2.4, 8.3 Hz), 7.24-7.30 (2H, m), 7.40-7.47 (2H, m), 7.81 (1H, d, J = 8.7 Hz), 8.19 (1H, dd, J = 2.5, 8.3 Hz), 8.74 (1H, d, J = 2.4 Hz), DMSO: 437 (M + H)⁺FAB 014 1.50-1.70 (2H, br), 1.89 (2H, d, J = 12.7 Hz), 3.11 (1H, t, J = 11.7 Hz), 3.27 (1H, t, J = 11.7 Hz), 3.75 (1H, tt, J = 3.2, 11.3 Hz), 4.07 (1H, d, J = 11.7 Hz), 4.23 (1H, d, J = 11.7 Hz), 7.45 (1H, dd, J = 5.4, 8.3 Hz), 7.57 (2H, t, J = 7.8 Hz), 7.63-7.69 (2H, m), 8.03 (2H, dd, J = 1.4, 8.3 Hz), 8.44 (2H, dd, J = 1.4, 4.9 Hz), DMSO: 311 (M + H)⁺FAB

TABLE 36 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 015 1.55-1.75 (2H, br), 1.83 (2H, d, J = 12.2 Hz), 2.81 (1H, tt, J = 3.4, 12.2 Hz), 4.15 (1H, d, J = 12.2 Hz), 4.31 (1H, d, J = 12.2 Hz), 7.10-7.17 (2H, m), 7.31-7.37 (2H, m), 7.44-7.48 (1H, m), 7.63-7.67 (1H, m), 8.43-8.46 (2H, m), DMSO: 301 (M + H)⁺FAB 016 326 (M + H)⁺FAB 017 2.46-2.62 (6H, m), 2.72-2.80 (2H, m), 3.40-3.50 (2H, br), 3.57-3.65 (2H, br), 7.16-7.32 (5H, m), 7.45 (1H, dd, J = 4.6, 8.3), 7.61-7.65 (1H, m), 8.42-8.45 (2H, m), DMSO: 312 (M + H)⁺FAB 018 1.60-1.75 (2H, br), 1.95-2.10 (2H, br), 3.33-3.41 (1H, br), 3.47-3.56 (1H, br), 3.69-3.78 (1H, br), 3.84-4.03 (1H, br), 5.96 (2H, s), 6.46 (1H, dd, J = 2.4, 8.7 Hz), 6.73 (1H, d, J = 2.4 Hz), 6.82 (1H, d, J = 8.7 Hz), 7.74-7.78 (1H, m), 8.04 (1H, d, J = 8.3 Hz), 8.62 (1H, d, J = 4.9 Hz), 8.72 (1H, s), DMSO: 343 (M + H)⁺FAB 019 1.20-1.40 (2H, br), 1.79-1.89 (2H, br), 1.94-2.04 (1H, m), 2.94 (1H, t, J = 11.8 Hz), 3.07 (1H, t, J = 11.8 Hz), 3.80 (2H, d, J = 6.3 Hz), 4.05 (1H, d, J = 11.8 Hz), 4.22 (1H, d, J = 11.8 Hz), 5.95 (2H, s), 6.37 (1H, dd, J = 2.5, 8.3 Hz), 6.64 (1H, d, J = 2.5 Hz), 6.80 (1H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 4.9, 8.3 Hz), 7.630 (1H, d, J = 8.3 Hz), 8.40-8.45 (2H, m), DMSO: 357 (M + H)⁺FAB 020 1.16-1.32 (2H, br), 1.64-1.82 (3H, m), 2.92 (1H, t, J = 11.7 Hz), 3.06 (1H, t, J = 11.7 Hz), 3.96 (2H, t, J = 6.4 Hz), 4.01 (1H, d, J = 11.7 Hz), 4.17 (1H, d, J = 11.7 Hz), 5.95 (2H, s), 6.37 (1H, dd, J = 2.5, 8.3 Hz), 6.63 (1H, d, J = 2.5 Hz), 6.80 (1H, d, J = 8.3 Hz), 7.74-7.80 (1H, m), 8.02-8.07 (1H, m), 8.61 (1H, d, J = 5.4 Hz), 8.71 (1H, brs), DMSO: 371 (M + H)⁺FAB 021 1.63-1.80 (2H, br), 1.97-1.99 (2H, br), 3.35-3.45 (1H, br), 3.50-3.60 (1H, br), 3.71-3.79 (1H, br), 3.86-3.95 (1H, br), 4.63-4.70 (1H, m), 6.94 (1H, t, J = 7.3 Hz), 7.01 (2H, d, J = 8.3 Hz), 7.30 (2H, t, J = 7.3 Hz), 7.76 (1H, dd, J = 4.8, 8.3 Hz), 8.05 (1H, d, J = 8.3 Hz), 8.62 (1H, d, J = 4.8 Hz), 8.73 (1H, s), DMSO: 299 (M + H)⁺FAB 022 2.85-2.98 (2H, m), 3.68 (1H, t, J = 4.9 Hz), 3.84 (1H, t, J = 5.8 Hz), 4.62 (1H, s), 4.82 (1H, s), 7.20-7.28 (4H, m), 7.46 (1H, dd, J = 4.4, 8.3 Hz), 7.65-7.69 (1H, m), 8.44-8.47 (2H, m), DMSO: 255 (M + H)⁺FAB 023 3.20-3.24 (4H, br), 3.55-3.65 (2H, br), 3.72-3.80 (2H, br), 6.83 (1H, t, J = 7.1), 7.00 (2H, d, J = 8.3), 7.25 (2H, t, J = 7.3), 7.46 (1H, dd, J = 4.4, 8.3), 7.63-7.69 (1H, m), 8.43-8.46 (2H, m), DMSO: 284 (M + H)⁺FAB 024 1.61-1.80 (2H, m), 1.97-2.12 (2H, m), 3.28-3.62 (2H, m), 3.68-3.99 (2H, m), 4.71-4.80 (1H, m), 7.05 (2H, d, J = 8.8 Hz), 7.12-7.22 (1H, m), 7.45 (1H, dd, J = 4.9 Hz, 8.3 Hz), 7.61-7.68 (1H, m), 7.78-7.88 (3H, m), 8.41-8.46 (2H, m), DMSO: 342 (M + H)⁺FAB 025 356 (M + H)⁺FAB 026 370 (M + H)⁺FAB 027 342 (M + H)⁺FAB

TABLE 37 Ex. DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 028 356 (M + H)⁺FAB 029 481 (M + H)⁺FAB 030 1.60-1.78 (2H, m), 1.93-2.06 (2H, m), 3.04 (6H, s), 3.30-3.93 (4H, m), 4.49-4.56 (1H, m), 5.07 (2H, s), 6.96 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.52 (2H, m), 8.05-8.08 (2H, m), DMSO: 466 (M + H)⁺FAB 031 424 (M + H)⁺FAB 032 2.04-2.20 (1H, m), 2.40-2.60 (1H, m), 3.10-4.10 (8H, m), 4.32-4.44 (2H, m), 7.41-7.50 (3H, m), 7.66-7.82 (2H, m), 8.05-8.16 (1H, m), 8.62 (1H, br), 8.80 (1H, d, J = 12.7 Hz), 11.58 (1H, br), DMSO: 312 (M + H)⁺FAB 033 1.25-1.35 (2H, m), 1.55-1.66 (2H, m), 1.70-1.83 (2H, m), 2.60 (2H, t, J = 7.3 Hz), 3.00-3.22 (4H, m), 3.40-3.70 (4H, m), 4.00-4.35 (2H, m), 7.15-7.33 (5H, m), 7.62 (1H, br), 7.85 (1H, br), 8.50-8.65 (2H, m), 10.90-11.40 (1H, br), DMSO: 354 (M + H)⁺FAB 034 3.09 (4H, br), 3.50-3.80 (4H, m), 5.04 (2H, s), 6.94 (4H, d, J = 1.7 Hz), 7.30-7.49 (6H, m), 7.63-7.68 (1H, m), 8.43-8.46 (2H, m), DMSO: 390 (M + H)⁺FAB 035 1.10-1.32 (2H, m), 1.46-1.60 (3H, m), 1.80 (2H, d, J = 11.7 Hz), 2.62 (2H, t, J = 7.8 Hz), 2.88 (1H, t, J = 12.2 Hz), 3.03 (1H, t, J = 12.2 Hz), 4.17 (1H, t, J = 12.2 Hz), 7.16-7.23 (3H, m), 7.27-7.31 (2H, m), 7.89 (1H, dd, J = 5.3, 8.8 Hz), 8.18-8.22 (1H, m), 8.69 (1H, dd, J = 1.0, 5.3 Hz), 8.82 (1H, d, J = 2.5 Hz), DMSO: 311 (M + H)⁺FAB 036 1.52-1.68 (2H, br), 1.88-2.01 (2H, br), 3.22-3.33 (1H, br), 3.37-3.48 (1H, br), 3.65-3.75 (2H, m), 3.82-3.91 (1H, br), 4.56 (2H, s), 7.26-7.32 (1H, m), 7.36 (4H, d, J = 4.4 Hz), 7.70 (1H, dd, J = 4.9, 8.3 Hz), 7.95 (1H, dd, J = 1.0, 8.3 Hz), 8.58 (1H, d, J = 4.9 Hz), 8.66 (1H, s), DMSO: 313 (M + H)⁺FAB 037 1.69 (2H, d, J = 12.7 Hz), 1.91-2.11 (2H, m), 3.33 (1H, t, J = 12.7 Hz), 3.47 (1H, t, J = 12.7 Hz), 3.93-4.07 (2H, m), 4.13 (1H, d, J = 12.7 Hz), 7.23 (1H, t, J = 7.4 Hz), 7.35 (2H, t, J = 7.4 Hz), 7.52-7.55 (2H, m), 7.81 (1H, dd, J = 5.4, 8.3 Hz), 8.10-8.14 (1H, m), 8.63 (1H, d, J = 4.9 Hz), 8.77 (1H, d, J = 2.4 Hz), DMSO: 299 (M + H)⁺FAB 038 2.58 (1H, br), 2.64 (1H, br), 3.67 (1H, br), 3.83 (1H, br), 4.13 (1H, s), 4.32 (1H, s), 6.21 (1H, s), 7.29 (1H, t, J = 7.3 Hz), 7.37 (2H, t, J = 7.3 Hz), 7.44-7.50 (3H, m), 7.67 (1H, d, J = 8.3 Hz), 8.44-8.47 (2H, m), DMSO: 281 (M + H)⁺FAB 039 1.95 (3H, s), 2.00-2.16 (2H, br), 2.39-2.47 (2H, br), 3.20-3.30 (1H, br), 3.35-3.45 (1H, br, 3.63-3.73 (1H, br), 3.79-3.89 (1H, br), 7.29-7.34 (1H, m), 7.37-7.46 (5H, m), 7.60-7.64 (1H, m), 8.40-8.43 (2H, m), DMSO: 325 (M + H)⁺FAB

TABLE 38 Ex. DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 040 1.61-1.81 (2H, m), 1.83 (2H, d, J = 12.2 Hz), 2.77-2.87 (1H, m), 3.05 (1H, t, J = 12.2 Hz), 3.19 (1H, t, J = 12.2 Hz), 4.16 (1H, d, J = 12.2 Hz), 4.33 (1H, d, J = 12.2 Hz), 7.19-7.24 (1H, m), 7.27-7.36 (5H, m), 7.91 (1H, dd, J = 5.3, 8.3 Hz), 7.36 (1H, d, J = 8.3 Hz), 8.70 (1H, d, J = 4.9 Hz), 8.85 (1H, s), DMSO: 283 (M + H)⁺FAB 041 35 (M + H)⁺FAB 042 1.60-1.76 (2H, m), 1.92-2.05 (2H, m), 3.30-3.92 (4H, m), 4.48-4.55 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.23-7.30 (2H, m), 7.39-7.48 (1H, m), 7.93-7.96 (1H, m), 8.44 (1H, d, J = 2.0 Hz), 8.52 (1H, d, J = 2.0 Hz), DMSO: 457 (M + H)⁺FAB 043 1.14-1.35 (2H, m), 1.68-1.84 (5H, m), 2.89 (1H, t, J = 11.7 Hz), 3.05 (1H, t, J = 11.7 Hz), 3.96-4.21 (4H, m), 6.98 (2H, d, J = 8.8 Hz), 7.16 (1H, brs), 7.44 (1H, dd, J = 4.9, 8.3 Hz), 7.60-7.65 (1H, m), 7.76-7.87 (3H, m), 8.40-8.44 (2H, m), DMSO: 370 (M + H)⁺FAB 044 1.60-1.75 (2H, m), 1.92-2.05 (2H, m), 3.30-3.92 (4H, m), 4.46-4.55 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.24-7.29 (2H, m), 7.40-7.47 (1H, m), 8.06-8.086 (1H, m), 8.47 (1H, d, J = 2.0 Hz), 8.59 (1H, d, J = 2.0 Hz), DMSO: 501 (M⁺)FAB 045 1.60-1.78 (2H, m), 1.93-2.06 (2H, m), 3.31-3.57 (6H, m), 3.70-3.93 (6H, m), 4.49-4.56 (1H, m), 5.07 (2H, s), 6.96 (4H, s), 7.12-7.17 (1H, m), 7.24-7.30 (2H, m), 7.41-7.47 (1H, m), 7.78 (1H, s), 8.19-8.22 (1H, m), 8.30-8.33 (1H, m), DMSO: 508 (M + H)⁺FAB 046 1.51-1.70 (2H, m), 1.87-2.02 (2H, m), 3.20-3.31 (1H, m), 3.36-3.47 (1H, m), 3.62-3.72 (1H, m), 3.66-3.77 (1H, m), 3.80-3.93 (1H, m), 4.61 (2H, s), 7.33 (1H, br s), 7.42 (2H, d, J = 8.3 Hz), 7.44 (1H, dd, J = 8.3, 4.4 Hz), 7.63 (1H, ddd, J = 8.3, 2.4, 1.5 Hz), 7.86 (2H, d, J = 8.3 Hz), 7.94 (1H, br s), 8.42 (1H, s), 8.43 (1H, dd, J = 6.3, 1.5 Hz), DMSO: 356 (M + H)⁺FAB 047 340 (M + H)⁺FAB 048 390 (M + H)⁺FAB 049 1.40-1.52 (2H, m), 1.55-1.65 (2H, m), 2.30-2.45 (4H, m), 2.60 (2H, t, J = 7.6 Hz), 3.38-3.64 (4H, m), 7.12-7.22 (3H, m), 7.25-7.31 (2H, m), 7.44 (1H, dd, J = 4.8, 7.5 Hz), 7.60-7.65 (1H, m), 8.40-8.45 (2H, m), DMSO: 340 (M + H)⁺FAB 050 308 (M + H)⁺FAB 051 1.60-1.84 (2H, br), 1.92-2.06 (2H, br), 3.40-3.52 (1H, br), 3.55-3.75 (2H, br), 3.79-3.91 (1H, br), 4.59-4.65 (1H, m), 5.08 (2H, s), 6.97 (1H, dd, J = 2.9, 9.3 Hz), 7.15 (1H, d, J = 2.9 Hz), 7.22 (1H, d, J = 8.8 Hz), 7.31-7.47 (5H, m), 7.88 (1H, dd, J = 5.4, 8.8 Hz), 8.20 (1H, d, J = 8.3 Hz), 8.68 (1H, d, J = 5.4 Hz), 8.83 (1H, d, J = 1.9 Hz), DMSO: 439 (M + H)⁺FAB

TABLE 39 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 052 311 (M + H)⁺FAB 053 1.07-1.27 (2H, m), 1.53 (2H, q, J = 6.4 Hz), 1.62-1.76 (3H, m), 2.90 (1H, t, J = 13.2 Hz), 3.04 (1H, t, J = 13.2 Hz), 3.50 (2H, t, J = 6.4 Hz), 3.99 (1H, d, J = 13.2 Hz), 4.15 (1H, d, J = 13.2 Hz), 4.46 (2H, s), 7.26-7.39 (5H, m), 7.73-7.78 (1H, m), 8.03 (1H, d, J = 8.3 Hz), 8.62 (1H, d, J = 4.4 Hz), 8.70 (1H, s), DMSO: 341 (M + H)⁺FAB 054 374, 376 (M + H)⁺FAB 055 1.10-1.30 (2H, m), 1.64 (2H, d, J = 13.2 Hz), 1.71-1.83 (1H, m), 2.56 (2H, d, J = 7.4 Hz), 2.83 (1H, t, J = 12.2 Hz), 2.98 (1H, t, J = 12.2 Hz), 3.36 (3H, s), 3.99 (1H, d, J = 12.2 Hz), 4.15 (1H, d, J = 12.2 Hz), 4.65 (2H, s), 7.17-7.22 (3H, m), 7.27-7.32 (2H, m), 7.43 (1H, d, J = 8.8 Hz), 7.60 (1H, dd, J = 2.5, 8.8 Hz), 8.33 (1H, d, J = 2.5 Hz), DMSO: 341 (M + H)⁺FAB 056 523 (M + H)⁺FAB 057 342 (M + H)⁺FAB 058 471 (M + H)⁺FAB 059 389 (M + H)⁺FAB 060 299 (M + H)⁺FAB 061 1.58-1.75 (2H, m), 1.90-2.04 (2H, m), 2.69 (2H, t, J = 7.8 Hz), 2.89 (2H, t, J = 7.8 Hz), 3.30-3.91 (7H, m), 4.47-4.55 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.23-7.30 (2H, m), 7.39-7.47 (1H, m), 7.51-7.55 (1H, m), 8.24-8.27 (1H, m), 8.30-8.34 (1H, m), DMSO: 509 (M + H)⁺FAB 062 356 (M + H)+FAB 063 1.07-1.31 (2H, m), 1.42-1.55 (1H, m), 1.52-1.64 (2H, m), 1.72-1.86 (2H, m), 2.68 (2H, t, J = 7.5 Hz), 2.78-2.91 (1H, m), 2.94-3.07 (1H, m), 3.93-4.07 (1H, m), 4.09-4.23 (1H, m), 7.26 (1H, br s), 7.29 (2H, d, J = 8.6 Hz), 7.44 (1H, dd, J = 8.6, 4.8 Hz), 7.61 (1H, ddd, J = 8.6, 2.7, 1.5 Hz), 7.80 (2H, d, J = 8.0 Hz), 7.89 (1H, br s), 8.41 (1H, d, J = 2.7 Hz), 8.42 (1H, dd, J = 4.8, 1.1 Hz), DMSO: 354 (M + H)⁺FAB 064 354 (M + H)⁺FAB 065 1.34-1.57 (2H, m), 1.78-1.90 (2H, m), 2.40-2.48 (1H, m), 2.92-3.08 (1H, m), 3.07-3.23 (1H, m), 3.98-4.13 (1H, m), 4.14-4.28 (1H, m), 6.44 (1H, dd, J = 16.1, 5.9 Hz), 6.50 (1H, d, J = 16.1 Hz), 7.30 (1H, br s), 7.45 (1H, dd, J = 8.3, 4.4 Hz), 7.48 (2H, d, J = 8.3 Hz), 7.63 (1H, ddd, J = 8.3, 2.5, 1.5 Hz), 7.83 (2H, d, J = 8.3 Hz), 7.92 (1H, br s), 8.43 (1H, d, J = 1.9 Hz), 8.43 (1H, dd, J = 4.4, 1.9 Hz), DMSO: 352 (M + H)⁺FAB 066 1.03-1.23 (2H, m), 1.35-1.43 (2H, m), 1.46-1.62 (1H, m), 1.72-1.87 (4H, m), 2.82-2.92 (3H, m), 3.03 (1H, t, J = 11.8 Hz), 3.74 (3H, s), 4.01 (1H, d, J = 11.8 Hz), 4.17 (1H, d, J = 11.8 Hz), 7.11-7.21 (2H, m), 7.42-7.49 (2H, m), 7.52-7.56 (1H, m), 7.59-7.63 (1H, m), 8.40-8.44 (2H, m), DMSO: 379 (M + H)⁺ESI

TABLE 40 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 067 308 (M + H)⁺FAB 068 339 (M + H)⁺FAB 069 1.04-1.26 (2H, m), 1.35-1.45 (2H, m), 1.48-1.61 (1H, m), 1.70-1.83 (4H, m), 2.80-2.94 (1H, m), 2.94-3.10 (1H, m), 3.96-4.06 (1H, m), 4.03 (2H, t, J = 6.4 Hz), 4.12-4.22 (1H, m), 6.96 (2H, d, J = 8.8 Hz), 7.15 (1H, br s), 7.44 (1H, dd, J = 8.3, 4.9 Hz), 7.61 (1H, ddd, J = 8.3, 2.9, 1.5 Hz), 7.81 (1H, br s), 7.83 (2H, d, J = 8.8 Hz), 8.41 (1H, d, J = 2.4 Hz), 8.42 (1H, dd, J = 4.9, 1.4 Hz), DMSO: 384 (M + H)⁺FAB 070 1.57-1.75 (2H, br), 1.90-2.06 (2H, br), 3.30-3.42 (1H, br), 3.45-3.56 (1H, br), 3.65-3.78 (1H, br), 3.80-3.95 (1H, br), 4.55-4.61 (1H, m), 5.14 (2H, s), 6.95 (1H, dd, J = 2.9, 9.3 Hz), 7.14-7.18 (2H, m), 7.31-7.48 (6H, m), 7.62-7.67 (1H, m), 8.42-8.45 (2H, m), DMSO: 439 (M + H)⁺FAB 071 486 (M + H)⁺FAB 072 385 (M + H)⁺FAB 073 578 (M + H)⁺FAB 074 313 (M + H)⁺FAB 075 441 (M + H)⁺FAB 076 439 (M + H)⁺FAB 077 1.21 (3H, t, J = 7.4 Hz), 1.58-1.78 (2H, m), 1.83 (2H, d, J = 12.7 Hz), 2.77 (1H, tt, J = 3.8, 12.2 Hz), 2.98 (1H, t, J = 12.2 Hz), 3.14 (1H, t, J = 12.2 Hz), 4.10-4.21 (3H, m), 4.31 (1H, d, J = 12.2 Hz), 4.76 (2H, s), 6.76 (1H, dd, J = 2.0, 7.4 Hz), 6.87 (1H, t, J = 2.0 Hz), 6.90 (1H, d, J = 7.4 Hz), 7.23 (1H, t, J = 7.8 Hz), 7.46 (1H, dd, J = 4.9, 8.3 Hz), 7.64-7.67 (1H, m), 8.42-8.47 (2H, br), DMSO: 385 (M + H)⁺FAB 078 1.58-1.78 (2H, m), 1.83 (2H, d, J = 12.2 Hz), 2.77 (1H, tt, J = 3.4, 12.2 Hz), 2.98 (1H, t, J = 12.2 Hz), 3.14 (1H, t, J = 12.2 Hz), 4.15 (1H, d, J = 12.2 Hz), 4.31 (1H, d, J = 12.2 Hz), 5.10 (2H, s), 6.84-6.90 (2H, m), 6.95 (1H, t, J = 2.0 Hz), 7.23 (1H, t, J = 7.8 Hz), 7.31-7.48 (6H, m), 7.64-7.67 (1H, m), 8.42-8.47 (2H, m), DMSO: 389 (M + H)⁺FAB 079 461 (M + H)⁺FAB 080 1.40-1.66 (2H, m), 1.88-2.00 (2H, m), 2.82-2.97 (1H, m), 2.97-3.14 (1H, m), 3.47-3.57 (1H, m), 4.01-4.17 (1H, m), 4.18-4.33 (1H, m), 5.26 (2H, s), 7.16-7.23 (1H, m), 7.30 (2H, d, J = 9.0 Hz), 7.30-7.36 (2H, m), 7.41-7.46 (1H, m), 7.45-7.51 (1H, m), 7.62 (1H, ddd, J = 8.3, 2.7, 1.5 Hz), 7.81 (2H, d, J = 8.8 Hz), 8.40 (1H, d, J = 2.4 Hz), 8.42 (1H, dd, J = 4.7, 1.5 Hz), DMSO: 471 (M + H)⁺FAB 081 1.10-1.34 (2H, m) 1.70-1.80 (2H, m), 1.80-1.92 (1H, m), 2.80-2.95 (1H, m), 2.95-3.10 (1H, m), 2.70-3.95 (1H, br s), 3.34 (2H, d, J = 6.4 Hz), 3.95-4.07 (1H, m), 4.11-4.23 (1H, m), 4.48 (2H, s), 7.25-7.38 (7H, m), 7.44 (1H, dd, J = 8.3, 4.6 Hz), 7.62 (1H, ddd, J = 8.3, 2.6 1.2 Hz), DMSO: 327 (M + H)⁺AFB 082 462 (M⁺)FAB 083 418 (M + H)⁺FAB

TABLE 41 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 084 326 (M + H)⁺FAB 085 2.49-2.62 (6H, m), 2.73-2.81 (2H, m), 3.40-3.66 (4H, m), 7.15-7.32 (5H, m), 7.93 (1H, t, J = 1.9 Hz), 8.44 (1H, d, J = 2.4 Hz), 8.52 (1H, d, J = 2.0 Hz), DMSO: 346 (M + H)⁺FAB 086 2.49-2.62 (6H, m), 2.73-2.81 (2H, m), 3.46 (2H, br), 3.62 (2H, br), 3.90 (3H, s), 7.15-7.32 (5H, m), 8.11 (1H, dd, J = 2.0, 2.7 Hz), 8.70 (1H, d, J = 2.8 Hz), 8.94 (1H, d, J = 1.7 Hz), DMSO: 370 (M + H)⁺FAB 087 1.63-1.80 (2H, br), 1.97-2.11 (2H, br), 3.33-3.41 (1H, br), 3.43-3.58 (1H, br), 3.68-3.82 (1H, br), 3.83-3.96 (1H, br), 4.72-4.80 (1H, m), 7.43-7.48 (2H, m), 7.59 (1H, dd, J = 3.2, 8.8 Hz), 7.62-7.67 (1H, m), 8.19 (1H, d, J = 2.2 Hz), 8.43-8.45 (2H, m), DMSO: 334 (M + H)⁺FAB 088 1.39-1.65 (2H, m), 1.88-1.98 (2H, m), 2.83-3.13 (2H, m), 3.46-3.55 (1H, m), 4.03-4.33 (2H, m), 5.23 (2H, s), 7.29 (2H, d, J = 8.8 Hz), 7.33-7.51 (6H, m), 7.62 (1H, ddd, J = 1.5, 2.9, 8.3 Hz), 7.80 (2H, d, J = 8.8 Hz), 8.40 (1H, d, J = 2.4 Hz), 8.42 (1H, dd, J = 1.5, 4.9 Hz), DMSO: 453 (M + H)⁺FAB 089 1.40-1.65 (2H, m), 1.88-1.99 (2H, m), 2.83-3.14 (2H, m), 3.47-3.57 (1H, m), 4.03-4.34 (2H, m), 5.30 (2H, s), 7.31 (2H, d, J = 8.8 Hz), 7.44 (1H, dd, J = 4.9, 8.3 Hz), 7.59-7.68 (2H, m), 7.79-7.87 (4H, m), 7.96-7.98 (1H, m), 8.40 (1H, d, J = 2.4 Hz), 8.42 (1H, dd, J = 1.5, 4.9 Hz), DMSO: 478 (M + H)⁺FAB 090 469 (M + H)⁺FAB 091 473 (M + H)⁺FAB 092 334 (M + H)⁺FAB 093 424 (M + H)⁺FAB 094 419 (M + H)⁺FAB 095 487 (M + H)⁺FAB 096 385 (M + H)⁺FAB 097 437 (M + H)⁺FAB 098 1.06-1.26 (2H, m), 1.37-1.44 (2H, m), 1.50-1.60 (1H, m), 1.73-1.82 (4H, m), 2.86 (1H, t, J = 12.2 Hz), 2.94 (6H, s), 3.05 (1H, t, J = 12.2 Hz), 3.97-4.04 (3H, m), 4.18 (1H, d, J = 11.7 Hz), 6.96 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.73 (1H, dd, J = 4.8, 8.3 Hz), 7.96-8.01 (1H, m), 8.59 (1H, dd, J = 1.5, 4.8 Hz), 8.67 (1H, d, J = 2.4 Hz), DMSO: 412 (M + H)⁺FAB 099 1.02-1.22 (2H, m), 1.36-1.44 (2H, m), 1.49-1.61 (1H, m), 1.72-1.82 (4H, m), 2.75 (3H, d, J = 4.4 Hz), 2.87 (1H, t, J = 12.2 Hz), 3.02 (1H, t, J = 12.2 Hz), 3.98-4.05 (3H, m), 4.17 (1H, d, J = 12.2 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.43 (1H, dd, J = 4.4, 8.3 Hz), 7.59-7.64 (1H, m), 7.78 (2H, d, J = 8.3 Hz), 8.22-8.27 (1H, m), 8.38-8.43 (2H, m), DMSO: 398 (M + H)⁺FAB

TABLE 42 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 100 1.58-1.74 (2H, m), 1.90-2.06 (2H, m), 2.50 (3H, s), 3.30-3.95 (4H, m), 4.48-4.58 (3H, m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.47 (1H, m), 7.54-7.57 (1H, m), 8.27-8.34 (1H, m), 8.34-8.42 (1H, m), DMSO: 495 (M + H)⁺FAB 101 1.40-1.64 (2H, m), 1.90-2.03 (2H, m), 3.05-3.18 (1H, m), 3.20-3.34 (1H, m), 3.51-3.62 (1H, m), 3.88-4.01 (1H, m), 4.02-4.14 (1H, m), 5.16 (2H, s), 6.90-6.95 (1H, m), 6.98-7.03 (1H, m), 7.03-7.06 (1H, m), 7.13-7.19 (1H, m), 7.25-7.32 (3H, m), 7.41-7.47 (1H, m), 7.72 (1H, dd, J = 8.8, 5.4 Hz), 7.99 (1H, ddd, J = 8.3, 2.4, 1.0 Hz), 8.56-8.61 (1H, m), 8.67 (1H, d, J = 2.4 Hz), DMSO: 439 (M + H)⁺FAB 102 426 (M + H)⁺FAB 103 1.58-1.78 (2H, br), 1.97-2.11 (2H, br), 3.30-3.60 (2H, br), 3.70-3.79 (1H, br), 3.85-3.96 (1H, br), 5.11-5.16 (3H, m), 6.79 (1H, d, J = 8.8 Hz), 7.12-7.20 (1H, m), 7.25-7.30 (2H, m), 7.40-7.50 (3H, m), 7.61-7.67 (1H, m), 7.93 (1H, d, J = 3.5 Hz), 8.40-8.46 (2H, br), DMSO: 424 (M + H)⁺FAB 104 1.16-1.32 (2H, m) 1.70-1.82 (2H, m), 1.79-1.91 (1H, m), 2.82-2.99 (1H, m), 2.95-3.12 (1H, m), 3.34 (2H, d, J = 6.3 Hz), 3.98-4.07 (1H, m), 4.11 (2H, dd, J = 5.8, 1.4 Hz), 4.14-4.23 (1H, m), 6.36 (1H, ddd, J = 16.1, 5.8, 5.8 Hz), 6.61 (1H, d, J = 16.1 Hz), 6.63 (1H, s), 7.21-7.29 (1H, m), 7.30-7.38 (2H, m), 7.40-7.49 (3H, m), 7.61 (1H, ddd, J = 8.3, 2.4, 1.4 Hz), 8.37-8.64 (2H, m), 13.12 (1H, br s), DMSO: 353 (M + H)⁺FAB 105 471 (M + H)⁺FAB 106 424 (M + H)⁺FAB 107 313 (M + H)⁺FAB 108 1.04-1.24 (2H, br), 1.36-1.43 (2H, m), 1.48-1.61 (1H, m), 1.72-1.82 (4H, m), 2.87 (1H, t, J = 11.7 Hz), 3.03 (1H, t, J = 11.7 Hz), 4.01 (1H, d, J = 11.7 Hz), 4.07 (2H, t, J = 6.4 Hz), 4.17 (1H, d, J = 11.7 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.44 (1H, dd, J = 5.4, 8.3 Hz), 7.59-7.63 (1H, m), 7.76 (2H, d, J = 8.8 Hz), 8.40-8.44 (2H, m), DMSO: 366 (M + H)⁺FAB 109 223 (M + H)⁺FAB 110 1.23-1.43 (2H, m), 1.86 (2H, d, J = 12.7 Hz), 1.97-2.09 (1H, m), 2.93 (1H, t, J = 12.2 Hz), 3.09 (1H, t, J = 12.2 Hz), 3.88 (2H, d, J = 12.7 Hz), 4.07 (1H, d, J = 12.2 Hz), 4.23 (1H, d, J = 12.2 Hz), 6.90-6.96 (3H, m), 7.26-7.31 (2H, m), 7.44 (1H, dd, J = 4.4, 8.3 Hz), 7.61-7.65 (1H, m), 8.41-8.44 (2H, m), DMSO: 313 (M + H)⁺FAB 111 1.16-1.36 (2H, m), 1.67-1.85 (5H, m), 2.93 (1H, t, J = 12.2 Hz), 3.08 (1H, t, J = 12.2 Hz), 4.00 (1H, d, J = 12.2 Hz), 4.03 (2H, t, J = 6.3 Hz), 4.17 (1H, d, J = 12.2 Hz), 6.90-6.96 (3H, m), 7.26-7.31 (2H, m), 7.78 (1H, dd, J = 4.9, 8.3 Hz), 8.03-8.08 (1H, m), 8.62 (1H, dd, J = 1.0, 4.9 Hz), 8.72 (1H, d, J = 2.5 Hz), DMSO: 327 (M + H)⁺FAB

TABLE 43 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 112 1.05-1.25 (2H, m), 1.47-1.52 (2H, m), 1.58-1.68 (1H, m), 1.70-1.84 (4H, m), 2.62 (2H, t, J = 7.4 Hz), 2.87 (2H, t, J = 12.2 Hz), 3.03 (1H, t, J = 12.2 Hz), 4.00 (1H, d, J = 12.2 Hz), 4.15 (1H, d, J = 12.2 Hz), 7.15-7.22 (3H, m), 7.25-7.30 (2H, m), 7.45 (1H, dd, J = 4.9, 8.3 Hz), 7.59-7.64 (1H, m), 8.38-8.44 (2H, m), DMSO: 369 (M + H)⁺FAB 113 1.65-1.75 (2H, m), 1.83 (2H, d, J = 12.2 Hz), 1.98-2.05 (2H, m), 2.72-2.80 (3H, m), 2.98 (1H, t, J = 12.2 Hz), 3.14 (1H, t, J = 12.2 Hz), 3.97 (2H, t, J = 6.3 Hz), 4.15 (1H, d, J = 11.7 Hz), 4.31 (1H, d, J = 11.7 Hz), 6.75-6.79 (1H, m), 6.83-6.87 (2H, m), 7.16-7.32 (6H, m), 7.46 (1H, dd, J = 4.9, 8.8 Hz), 7.64-7.68 (1H, m), 8.42-8.47 (2H, br), DMSO: 417 (M + H)⁺FAB 114 1.10-1.26 (2H, m), 1.35-1.45 (2H, m), 1.48-1.62 (1H, m), 1.70-1.82 (4H, m), 2.80-2.95 (1H, m), 2.96-3.11 (1H, m), 3.96 (2H, t, J = 6.4 Hz), 3.97-4.07 (1H, m), 4.10-4.24 (1H, m), 6.89-6.95 (3H, m), 7.24-7.32 (2H, m), 7.44 (1H, dd, J = 8.3, 3.9 Hz), 7.61 (1H, ddd, J = 8.3, 2.9, 1.5 Hz), 8.40 (1H, d, J = 2.9 Hz), 8.42 (1H, dd, J = 4.4, 1.5 Hz), DMSO: 341 (M + H)⁺FAB 115 1.06-1.26 (2H, br), 1.37-1.45 (2H, m), 1.50-1.62 (1H, m), 1.72-1.88 (4H, m), 2.88 (1H, t, J = 13.2 Hz), 3.03 (1H, t, J = 13.2 Hz), 4.01 (1H, d, J = 11.7 Hz), 4.13 (2H, t, J = 6.3 Hz), 4.18 (1H, d, J = 11.7 Hz), 7.02 (1H, t, J = 7.8 Hz), 7.14 (1H, d, J = 7.8 Hz), 7.42-7.49 (2H, m), 7.53-7.64 (3H, m), 7.81 (1H, dd, J = 1.9, 7.8 Hz), 8.40-8.44 (2H, m), DMSO: 384 (M + H)⁺FAB 116 1.05-1.25 (2H, br), 1.36-1.45 (2H, m), 1.52-1.64 (1H, m), 1.73-1.83 (4H, m), 2.88 (1H, t, J = 12.7 Hz), 3.05 (1H, t, J = 12.7 Hz), 3.99-4.05 (3H, m), 4.18 (1H, d, J = 12.7 Hz), 7.05-7.09 (1H, m), 7.34 (2H, t, J = 8.3 Hz), 7.41-7.46 (2H, m), 7.73 (1H, dd, J = 4.9, 8.3 Hz), 7.92-8.02 (2H, m), 8.57-8.60 (1H, m), 8.67 (1H, d, J = 2.4 Hz), DMSO: 384 (M + H)⁺FAB 117 1.59-1.74 (2H, m), 1.96-2.03 (2H, m), 3.27-3.56 (2H, m), 3.70-3.95 (5H, m), 4.48-4.58 (3H, m), 5.08 (2H, s), 6.85 (1H, d, J = 16.1 Hz), 6.96 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.47 (1H, m), 7.72 (1H, d, J = 16.1 Hz), 8.10 (1H, dd, J = 1.5 Hz, 2.4 Hz), 8.46 (1H, d, J = 2.4 Hz), 8.75 (1H, d, J = 1.5 Hz), DMSO: 507 (M + H)⁺FAB 118 1.60-1.76 (2H, m), 1.92-2.05 (2H, m), 3.30-3.55 (2H, m), 3.66-3.93 (2H, m), 4.48-4.56 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.23-7.30 (2H, m), 7.39-7.47 (1H, m), 7.75-7.82 (1H, m), 8.35-8.40 (1H, m), 8.50 (1H, d, J = 2.5 Hz), DMSO: 441 (M + H)⁺FAB 119 452 (M + H)⁺FAB 120 449 (M + H)⁺FAB 121 437 (M + H)⁺FAB 122 0.96-1.27 (5H, m), 1.60-1.86 (6H, m), 3.26-3.82 (8H, m), 3.82 (2H, d, J = 6.3 Hz), 6.92-7.04 (3H, m), 7.36 (1H, t, J = 8.3 Hz), 7.62-7.69 (1H, m), 7.90 (1H, br), 8.50-8.66 (2H, m), DMSO: 424 (M + H)⁺FAB 123 437 (M + H)⁺FAB

TABLE 44 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 124 2.29 (3H, s), 2.68 (2H, t, J = 7.3 Hz), 2.84 (2H, t, J = 7.3 Hz), 3.37-3.62 (8H, m), 7.12 (2H, d, J = 7.9 Hz), 7.15-7.22 (1H, m), 7.24-7.32 (4H, m), 7.49 (2H, d, J = 7.8 Hz), 7.80 (1H, dd, J = 4.9, 8.3 Hz), 8.05-8.10 (1H, m), 8.63 (1H, dd, J = 1.0, 4.9 Hz), 8.73 (1H, d, J = 2.4 Hz), DMSO: 340 (M + H)⁺FAB 125 312 (M + H)⁺FAB 126 3.46-3.59 (2H, m), 3.61-3.77 (4H, m), 3.78-3.92 (2H, m), 7.30 (1H, d, J = 15.5 Hz), 7.36-7.45 (2H, m), 7.48 (1H, d, J = 8.0 Hz), 7.54 (1H, d, J = 15.5 Hz), 7.71-7.76 (1H, m), 7.80 (1H, dd, J = 8.6, 4.8 Hz), 8.07-8.12 (1H, m), 8.64 (1H, dd, J = 5.3, 1.1 Hz), 8.75 (1H, d, J = 2.2 Hz), DMSO: 338 (M + H)ES 127 342 (M + H)⁺ESI 128 326 (M + H)⁺FAB 129 341 (M + H)⁺ESI 130 354 (M + H)⁺FAB 131 352 (M + H)⁺FAB 132 369 (M + H)⁺FAB 133 355 (M + H)⁺FAB 134 426 (M + H)⁺FAB 135 457 (M + H)⁺FAB 136 457 (M + H)⁺FAB 137 453 (M + H)⁺FAB 138 3.30-3.82 (8H, br), 5.08 (2H, s), 7.02 (1H, d, J = 7.8), 7.06-7.08 (1H, m), 7.11-7.14 (1H, m), 7.38-7.47 (4H, m), 7.53 (1H, s), 7.70-7.80 (1H, br), 7.95-8.08 (1H, br), 8.58 (2H, m), DMSO: 452 (M + H)⁺FAB 139 385 (M + H)⁺ESI 140 385 (M + H)⁺ESI 141 385 (M + H)⁺ESI 142 348 (M + H)⁺FAB 143 362 (M + H)⁺FAB 144 2.29 (3H, s), 3.40-3.71 (8H, m), 5.12 (2H, s), 7.12 (2H, d, J = 7.8 Hz), 7.30-7.41 (5H, m), 7.49 (2H, d, J = 8.3 Hz), 7.80 (1H, dd, J = 5.4, 8.3 Hz), 8.02-8.11 (1H, m), 8.63 (1H, d, J = 5.4 Hz), 8.73 (1H, d, J = 1.9 Hz), DMSO: 342 (M + H)⁺FAB 145 329 (M + H)⁺FAB 146 341 (M + H)⁺FAB 147 3.44-3.71 (8H, m), 5.18 (2H, s), 7.10 (2H, d, J = 8.8 Hz), 7.38-7.50 (6H, m), 7.54 (1H, s), 7.61-7.67 (1H, m), 8.40-8.44 (2H, m), DMSO: 452 (M + H)⁺FAB 148 432 (M + H)⁺FAB 149 3.40-3.71 (8H, m), 5.28 (2H, s), 7.12 (2H, d, J = 8.8 Hz), 7.40-7.48 (3H, m), 7.62-7.68 (2H, m), 7.72 (1H, d, J = 7.8 Hz), 7.79 (1H, d, J = 7.3 Hz), 7.84 (1H, s), 8.42-8.46 (2H, m), DMSO: 486 (M + H)⁺FAB

TABLE 45 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 150 448 (M + H)⁺FAB 151 3.43-3.74 (8H, m), 5.23 (2H, s), 7.10 (2H, d, J = 8.8 Hz), 7.40-7.48 (3H, m), 7.60-7.67 (2H, m), 7.79-7.85 (2H, m), 7.95 (1H, br), 8.42-8.46 (2H, m), DMSO: 443 (M + H)⁺FAB 152 3.43-3.74 (8H, m), 5.20 (2H, s), 7.09 (2H, d, J = 8.8 Hz), 7.14-7.26 (3H, m), 7.40-7.49 (3H, m), 7.60-7.68 (1H, m), 8.42-8.46 (2H, m), DMSO: 454 (M + H)⁺FAB 153 502 (M + H)⁺FAB 154 3.42-3.74 (8H, m), 5.33 (2H, s), 7.13 (2H, d, J = 8.8 Hz), 7.42-7.49 (3H, m), 7.63-7.67 (1H, m), 7.72 (1H, t, J = 7.8 Hz), 7.94 (1H, d, J = 8.1 Hz), 8.19-8.23 (1H, m), 8.34 (1H, br), 8.42-8.46 (2H, m), DMSO: 463 (M + H)⁺ESI 155 3.43-3.74 (8H, m), 5.14 (2H, s), 7.07 (2H, d, J = 8.8 Hz), 7.23 (2H, t, J = 8.8 Hz), 7.40-7.56 (5H, m), 7.60-7.67 (1H, m), 8.40-8.46 (2H, m), DMSO: 436 (M + H)⁺FAB 156 436 (M + H)⁺FAB 157 419 (M + H)⁺FAB 158 439 (M + H)⁺ESI 159 3.43-3.74 (8H, m), 5.17 (2H, s), 7.10 (2H, d, J = 8.8 Hz), 7.38 (1H, t, J = 7.8 Hz), 7.40-7.50 (4H, m), 7.55 (1H, d, J = 7.8 Hz), 7.63-7.70 (2H, m), 8.42-8.47 (2H, m), DMSO: 496, (M + H)⁺FAB 160 3.07 (2H, t, J = 7.0 Hz), 3.43-3.74 (8H, m), 4.26 (2H, t, J = 6.6 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.24-7.48 (7H, m), 7.62-7.67 (1H, m), 8.42-8.46 (2H, m), DMSO: 466 (M + H)⁺FAB 161 443 (M + H)⁺FAB 162 544 (M + H)⁺FAB 163 461 (M + H)⁺FAB 164 477 (M + H)⁺FAB 165 477 (M + H)⁺FAB 166 473 (M + H)⁺FAB 167 476 (M + H)⁺FAB 168 346 (M + H)⁺FAB 169 307 (M + H)⁺FAB 170 1.00-1.20 (2H, m), 1.18-1.25 (2H, m), 1.35-1.50 (1H, m), 1.45-1.58 (2H, m), 1.68-1.78 (2H, m), 2.14 (2H, t, J = 7.4 Hz), 2.77-2.91 (1H, m), 2.92-3.09 (1H, m), 3.90-4.07 (1H, m), 4.10-4.22 (1H, m), 6.68 (1H, br s), 7.22 (1H, br s), 7.45 (1H, dd, J = 8.3, 4.9 Hz), 7.56-7.66 (1H, m), 8.25-8.50 (2H, m), DMSO: 292 (M + H)⁺FAB 171 354 (M + H)⁺FAB 172 341 (M + H)⁺FAB

TABLE 46 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 173 1.54-1.79 (2H, m), 1.82-1.96 (2H, m), 2.62 (1H, dddd, J = 11.2, 11.2, 3.4, 3.4 Hz), 2.88-3.07 (1H, m), 3.04-3.23 (1H, m), 4.00-4.16 (1H, m), 4.16-4.32 (1H, m), 6.99-7.07 (1H, m), 7.25-7.34 (2H, m), 7.45 (1H, dd, J = 8.3, 4.9 Hz), 7.58-7.65 (2H, m), 7.65 (1H, ddd, J = 8.3, 2.4, 1.4 Hz), 8.41-8.46 (2H, m), 9.94 (1H, s), DMSO: 326 (M + H)⁺FAB 174 1.42-1.65 (2H, m), 1.65-1.79 (2H, m), 2.35 (1H, dddd, J = 11.3, 11.3, 3.4, 3.4 Hz), 2.72 (2H, t, J = 7.3 Hz), 2.83-2.99 (1H, m), 3.00-3.16 (1H, m), 3.28 (2H, t, J = 7.3 Hz), 3.91-4.06 (1H, m), 4.08-4.23 (1H, m), 7.16-7.23 (3H, m), 7.25-7.33 (2H, m), 7.44 (1H, dd, J = 8.3, 4.9 Hz), 7.62 (1H, ddd, J = 8.3, 2.5, 1.0 Hz), 7.90 (1H, br t, J = 5.4 Hz), 8.41 (1H, d, J = 2.5 Hz), 8.43 (1H, dd, J = 4.9, 1.5 Hz), DMSO: 354 (M + H)⁺FAB 175 1.40 (2H, tt, J = 7.3, 7.3 Hz), 1.56 (2H, tt, J = 7.3, 7.3 Hz), 1.47-1.66 (2H, m), 1.68-1.79 (2H, m), 2.30-2.40 (1H, m), 2.57 (2H, t, J = 7.8 Hz), 2.86-2.94 (1H, m), 3.00-3.08 (1H, m), 3.07 (2H, dt, J = 6.9, 6.9 Hz), 3.93-4.07 (1H, m), 4.10-4.24 (1H, m), 7.12-7.21 (3H, m), 7.23-7.31 (2H, m), 7.44 (1H, dd, J = 8.3, 4.9 Hz), 7.62 (1H, ddd, J = 8.3, 3.0, 1.5 Hz), 7.81 (1H, br t, J = 5.4 Hz), 8.41 (1H, d, J = 2.4 Hz), 8.43 (1H, dd, J = 4.4, 3.0 Hz), DMSO: 382 (M + H)⁺FAB 176 0.85 (3H, t, J = 6.4 Hz), 1.17-1.32 (10H, m), 1.45-1.58 (2H, m), 1.54-1.76 (2H, m), 1.80-1.93 (2H, m), 2.51 (2H, t, J = 6.4 Hz), 2.55-2.64 (1H, m), 2.88-3.04 (1H, m), 2.99-3.20 (1H, m), 4.00-4.14 (1H, m), 4.15-4.30 (1H, m), 7.10 (2H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 8.3, 4.4 Hz), 7.50 (2H, d, J = 8.3 Hz), 7.64 (1H, ddd, J = 8.3, 2.5, 1.5 Hz), 8.40-8.46 (2H, m), 9.85 (1H, s), DMSO: 438 (M + H)⁺FAB 177 411 (M + H)⁺FAB 178 411 (M + H)⁺FAB 179 1.58-1.78 (2H, m), 1.85 (2H, d, J = 12.2 Hz), 2.75-2.83 (1H, m), 3.03 (1H, t, J = 12.2 Hz), 3.18 (1H, t, J = 12.2 Hz), 4.15 (1H, d, J = 12.7 Hz), 4.32 (1H, d, J = 12.7 Hz), 4.42 (2H, s), 6.80 (1H, dd, J = 2.0, 8.3 Hz), 6.88-6.92 (2H, m), 7.24 (1H, t, J = 8.3 Hz), 7.38 (1H, br), 7.52 (1H, br), 7.77 (1H, dd, J = 5.3, 8.3 Hz), 8.02-8.09 (1H, m), 8.62 (1H, d, J = 5.3 Hz), 8.74 (1H, d, J = 2.0 Hz), DMSO: 356 (M + H)⁺FAB 180 467 (M + H)⁺ESI 181 411 (M + H)⁺FAB 182 382 (M + H)⁺FAB 183 398 (M + H)⁺FAB 184 454 (M + H)⁺FAB 185 502 (M + H)⁺FAB 186 480 (M + H)⁺FAB 187 410 (M + H)⁺FAB 188 488 (M + H)⁺FAB 189 370 (M + H)⁺FAB 190 432 (M + H)⁺FAB

TABLE 47 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 191 397 (M + H)⁺FAB 192 409 (M + H)⁺ESI 193 386 (M + H)⁺FAB 194 371 (M + H)⁺FAB 195 357 (M + H)⁺ESI 196 337 (M + H)⁺FAB 197 1.20-1.32 (2H, m), 1.28-1.48 (2H, m), 1.47-1.62 (4H, m), 1.70-1.86 (2H, m), 2.06 (2H, t, J = 7.3 Hz), 2.56 (2H, t, J = 7.3 Hz), 2.98-3.10 (1H, m), 3.12-3.25 (1H, m), 3.73-3.86 (1H, m), 3.83-3.97 (1H, m), 3.98-4.13 (1H, m), 7.12-7.21 (3H, m), 7.22-7.30 (2H, m), 7.45 (1H, dd, J = 8.3, 4.4 Hz), 7.62 (1H, ddd, J = 8.3, 2.5, 1.5 Hz), 7.78 (1H, br d, J = 7.3 Hz), 8.41 (1H, d J = 2.5 Hz), 8.43 (1H, dd, J = 4.9, 1.5 Hz), DMSO: 396 (M + H)⁺FAB 198 315 (M + H)⁺FAB 199 1.57-1.75 (2H, br), 1.90-2.03 (2H, br), 3.28-3.40 (1H, br), 3.43-3.57 (1H, br), 3.64-3.79 (1H, br), 3.82-3.93 (1H, br), 4.38-4.46 (1H, m), 6.69 (2H, brd, J = 8.8 Hz), 6.83 (2H, brd, J = 8.8 Hz), 7.44 (1H, dd, J = 4.9, 8.3 Hz), 7.61-7.66 (1H, m), 8.43 (2H, d, J = 3.0 Hz), 8.96 (1H, s), DMSO: 315 (M + H)⁺FAB 200 0.96-1.30 (5H, m), 1.60-1.83 (8H, m), 1.94-2.09 (2H, m), 3.33-3.44 (1H, br), 3.48-3.60 (1H, br), 3.70-3.80 (1H, br), 3.75 (2H, d, J = 6.3 Hz), 3.85-3.95 (1H, br), 4.64-4.70 (1H, m), 6.50-6.60 (3H, m), 7.17 (1H, t, J = 13.7 Hz), 7.87 (1H, dd, J = 5.4, 8.3 Hz), 8.18 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 5.4 Hz), 8.82 (1H, d, J = 1.9 Hz), DMSO: 411 (M + H)⁺FAB 201 425 (M + H)⁺FAB 202 1.60-1.76 (2H, br), 1.95-2.07 (2H, br), 3.33-3.45 (1H, br), 3.47-3.58 (1H, br), 3.70-3.80 (1H, br), 3.85-3.96 (1H, br), 4.63-4.70 (1H, m), 5.13 (2H, s), 6.59-6.64 (3H, m), 7.13-7.23 (2H, m), 7.26-7.31 (2H, m), 7.41-7.48 (1H, m), 7.78 (1H, dd, J = 5.4, 8.8 Hz), 8.06 (1H, brd, J = 7.3 Hz), 8.62 (1H, d, J = 4.8 Hz), 8.73 (1H, d, J = 2.4 Hz), DMSO: 423 (M + H)⁺FAB 203 1.60-1.80 (2H, br), 1.90-2.07 (2H, br), 3.33-3.45 (1H, br), 3.47-3.60 (1H, br), 3.70-3.81 (1H, br), 3.85-3.96 (1H, br), 4.63-4.71 (1H, m), 5.12 (2H, s), 6.60-6.69 (3H, m), 7.18-7.28 (3H, m), 7.39-7.47 (1H, m), 7.56 (1H, dt, J = 1.4, 7.8 Hz), 7.83-7.89 (1H, m), 8.15-8.20 (1H, m), 8.68 (1H, brd, J = 5.4 Hz), 8.81 (1H, br), DMSO: 423 (M + H)⁺FAB 204 423 (M + H)⁺FAB 205 1.60-1.84 (2H, br), 1.94-2.06 (2H, br), 3.30-3.42 (1H, br), 3.45-3.56 (1H, br), 3.70-3.80 (1H, br), 3.84-3.96 (1H, br), 4.61-4.69 (1H, m), 5.16 (2H, m), 6.61 (1H, d, J = 2.5 Hz), 6.63 (1H, d, J = 2.5 Hz), 6.66 (1H, t, J = 1.9 Hz), 7.20 (1H, t, J = 7.8 Hz), 7.46 (1H, dd, J = 4.9, 8.3 Hz), 7.60-7.67 (2H, m), 7.78-7.83 (2H, m), 7.92 (1H, br), 8.45 (2H, m), DMSO: 430 (M + H)⁺FAB

TABLE 48 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 206 1.59-1.76 (2H, br), 1.91-2.07 (2H, br), 3.33-3.42 (1H, br), 3.45-3.56 (1H, br), 3.69-3.80 (1H, br), 3.82-3.94 (1H, br), 4.45-4.55 (1H, m), 5.06 (2H, s), 6.96 (4H, s), 7.36-7.46 (3H, m), 7.50 (1H, br), 7.75 (1H, dd, J = 4.9, 8.3 Hz), 8.02 (1H, d, J = 8.3 Hz), 8.60 (1H, d, J = 4.9 Hz), 8.70 (1H, d, J = 2.5 Hz), DMSO: 439 (M + H)⁺FAB 207 0.88-1.01 (2H, m), 1.09-1.30 (3H, m), 1.40-1.51 (1H, m), 1.55-1.76 (9H, m), 1.93-2.05 (2H, m), 3.30-3.42 (1H, br), 3.46-3.60 (1H, br), 3.70-3.80 (1H, br), 3.85-3.95 (3H, m), 4.45-4.55 (1H, m), 6.84-6.94 (4H, m), 7.66 (1H, dd, J = 4.9, 8.3 Hz), 7.98 (1H, d, J = 8.3 Hz), 8.58 (1H, d, J = 4.8 Hz), 8.66 (1H, d, J = 1.9 Hz), DMSO: 425 (M + H)⁺FAB 208 1.60-1.80 (2H, br), 1.94-2.07 (2H, br), 3.31-3.44 (1H, br), 3.46-3.60 (1H, br), 3.69-3.82 (1H, br), 3.84-3.96 (1H, br), 4.50-4.58 (1H, m), 5.08 (2H, s), 6.97 (4H, s), 7.20-7.28 (2H, m), 7.39-7.45 (1H, m), 7.54 (1H, dt, J = 1.5, 7.3 Hz), 7.81 (1H, dd, J = 5.4, 8.3 Hz), 8.10 (1H, brd, J = 8.3 Hz), 8.64 (1H, d, J = 5.3 Hz), 8.77 (1H, s), DMSO: 423 (M + H)⁺FAB 209 1.60-1.80 (2H, br), 1.94-2.07 (2H, br), 3.31-3.44 (1H, br), 3.46-3.60 (1H, br), 3.69-3.80 (1H, br), 3.82-3.96 (1H, br), 4.48-4.58 (1H, m), 5.03 (2H, s), 6.96 (4H, s), 7.18-7.26 (2H, m), 7.45-7.51 (2H, m), 7.78-7.89 (1H, m), 8.07-8.19 (1H, m), 8.67 (1H, brd, J = 4.9 Hz), 8.80 (1H, br), DMSO: 423 (M + H)⁺FAB 210 1.60-1.75 (2H, br), 1.91-2.06 (2H, br), 3.30-3.42 (1H, br), 3.45-3.56 (1H, br), 3.70-3.80 (1H, br), 3.84-3.96 (1H, br), 4.49-4.56 (1H, m), 5.11 (2H, m), 6.96 (4H, s), 7.46 (1H, dd, J = 4.8, 8.6 Hz), 7.61 (1H, t, J = 7.5 Hz), 7.64-7.68 (1H, m), 7.76-7.83 (2H, m), 7.90 (1H, br), 8.43-8.47 (2H, m), DMSO: 430 (M + H)⁺FAB 211 463 (M + H)⁺FAB 212 1.58-1.74 (2H, br), 1.91-2.05 (2H, br), 3.30-3.42 (1H, br), 3.45-3.55 (1H, br), 3.65-3.79 (1H, br), 3.83-3.94 (1H, br), 4.48-4.55 (1H, m), 5.09 (2H, s), 6.96 (4H, s), 7.36-7.50 (3H, m), 7.59 (1H, d, J = 7.9 Hz), 7.62-7.66 (1H, m), 7.84 (1H, d, J = 7.8 Hz), 7.96 (1H, s), 8.00 (1H, br), 8.41-8.45 (2H, m), DMSO: 448 (M + H)⁺FAB 213 497 (M + H)⁺FAB 214 484 (M + H)⁺FAB 215 488 (M + H)⁺FAB 216 0.96-1.08 (2H, m), 1.10-1.31 (3H, m), 1.60-1.83 (8H, m), 1.91-2.05 (2H, m), 3.25-3.57 (2H, m), 3.65-3.95 (7H, m), 4.46-4.54 (1H, m), 6.81-6.87 (2H, m), 6.89-6.95 (2H, m), 8.13 (1H, dd, J = 2.0 Hz, 2.4 Hz), 8.70 (1H, d, J = 2.4 Hz), 8.94 (1H, d, J = 2.0 Hz), DMSO: 469 (M + H)⁺FAB 217 1.58-1.76 (2H, m), 1.90-2.04 (2H, m), 2.80-4.00 (4H, m), 4.38-4.47 (1H, m), 6.70 (2H, d, J = 8.8 Hz), 6.83 (2H, d, J = 8.8 Hz), 8.05-8.10 (1H, m), 8.66 (1H, d, J = 2.4 Hz), 8.90-8.94 (1H, m), DMSO: 359 (M + H)⁺FAB

TABLE 49 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 218 1.60-1.78 (2H, m), 1.93-2.05 (2H, m), 3.35-3.95 (4H, m), 4.48-4.56 (1H, m), 5.07 (2H, s), 6.96 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.47 (1H, m), 8.07-8.10 (1H, m), 8.67 (1H, d, J = 2.4 Hz), 8.91-8.94 (1H, m), 13.30-13.75 (1H, br), DMSO: 467 (M + H)⁺FAB 219 341 (M + H)⁺FAB 220 327 (M + H)⁺ESI 221 449 (M + H)⁺FAB 222 325 (M + H)⁺ESI 223 353 (M − H)⁻FAB 224 355 (M − H)⁻FAB 225 1.12-1.32 (2H, m), 1.45-1.60 (3H, m), 1.79 (2H, d, J = 11.7 Hz), 2.63 (2H, t, J = 7.5 Hz), 2.87 (1H, t, J = 12.2 Hz), 3.02 (1H, t, J = 12.2 Hz), 4.01 (1H, d, J = 12.7 Hz), 4.18 (1H, t, J = 12.7 Hz), 7.15-7.31 (5H, m), 8.05 (1H, dd, J = 2.0, 2.4 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.92 (1H, t, J = 2.0 Hz), 13.59 (1H, br s), DMSO: 355 (M + H)⁺FAB 226 470 (M + H)⁺FAB 227 410 (M + H)⁺FAB 228 0.88-1.00 (2H, m), 1.08-1.28 (4H, m), 1.39-1.51 (1H, m), 1.54-1.77 (10H, m), 1.91-2.05 (2H, m), 3.20-3.96 (6H, m), 4.46-4.54 (1H, m), 6.83-6.88 (2H, m), 6.90-6.95 (2H, m), 8.08 (1H, dd, J = 2.0 Hz, 2.4 Hz), 8.66 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 1.5 Hz), DMSO: 469 (M + H)⁺FAB 229 483 (M + H)⁺FAB 230 474 (M + H)⁺FAB 231 356 (M + H)⁺FAB 232 371 (M + H)⁺FAB 233 1.58-1.78 (2H, m), 1.91-2.06 (2H, m), 3.25-3.95 (7H, m), 4.49-4.56 (1H, m), 5.02 (2H, s), 6.86-7.03 (7H, m), 7.30 (1H, dd, J = 7.8 Hz, 8.3 Hz), 8.07 (1H, s), 8.64 (1H, s), 8.92 (1H, s), DMSO: 479 (M + H)⁺FAB 234 1.60-1.80 (2H, br), 1.92-2.10 (2H, br), 3.30-3.60 (2H, br), 3.70-3.80 (1H, br), 3.85-3.96 (1H, br), 4.60-4.70 (1H, m), 5.12 (2H, s), 6.58-6.68 (3H, m), 7.24-7.32 (4H, m), 7.42-7.50 (1H, m), 8.09 (1H, t, J = 2.4 Hz), 8.67 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 1.9 Hz), 13.50 (1H, br), DMSO: 467 (M + H)⁺FAB 235 1.60-1.80 (2H, br), 1.92-2.10 (2H, br), 3.30-3.60 (2H, br), 3.70-3.80 (1H, br), 3.85-3.96 (1H, br), 4.60-4.72 (1H, m), 5.16 (2H, s), 6.60-6.68 (3H, m), 7.21 (1H, t, J = 8.3 Hz), 7.62 (1H, t, J = 8.3 Hz), 7.78-7.84 (2H, m), 7.92 (1H, s), 8.09 (1H, dd, J = 1.4, 2.4 Hz), 8.67 (1H, d, J = 3.0 Hz), 8.93 (1H, d, J = 1.4 Hz), 13.50 (1H, br), DMSO: 474 (M + H)⁺FAB

TABLE 50 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 236 1.60-1.74 (2H, m), 1.91-2.06 (2H, m), 3.30-3.95 (7H, m), 4.47-4.57 (1H, m), 5.14 (2H, s), 6.96 (4H, s), 7.55 (1H, dd, J = 7.4 Hz, 7.8 Hz), 7.72 (1H, d, J = 7.4 Hz), 7.92 (1H, d, J = 7.8 Hz), 8.04 (1H, s), 8.08 (1H, dd, J = 2.0 Hz, 2.4 Hz), 8.67 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 2.0 Hz), DMSO: 507 (M + H)⁺FAB 237 455 (M + H)⁺FAB 238 369 (M + H)⁺ESI 239 385 (M + H)⁺ESI 240 371 (M + H)⁺ESI 241 398 (M + H)⁺FAB 242 0.73-2.10 (17H, m), 3.20-4.02 (6H, br), 4.60-4.70 (1H, m), 6.49-6.60 (3H, m), 7.17 (1H, t, J = 8.3 Hz), 8.09 (1H, br), 8.67 (1H, d, J = 2.0 Hz), 8.92 (1H, br), 13.40-13.80 (1H, br), DMSO: 469 (M + H)⁺FAB 243 370 (M + H)⁺FAB 244 524 (M + H)⁺FAB 245 1.60-1.77 (2H, m), 1.92-2.06 (2H, m), 3.35-3.96 (4H, m), 4.48-4.56 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.47 (1H, m), 7.63-7.71 (1H, m), 8.07-8.10 (1H, m), 8.14-8.23 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 8.90 (1H, d, J = 1.9 Hz), DMSO: 466 (M + H)⁺FAB 246 1.59-1.78 (2H, m), 1.91-2.05 (2H, m), 3.25-3.57 (2H, m), 3.68-3.96 (2H, m), 4.47-4.56 (1H, m), 5.04 (2H, s), 6.95 (4H, s), 7.29-7.46 (5H, m), 7.64-7.70 (1H, m), 8.04 (1H, dd, J = 1.9 Hz, 2.4 Hz), 8.15-8.21 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.9 Hz), DMSO: 448 (M + H)⁺FAB 247 397 (M + H)⁺FAB 248 451 (M + H)⁺FAB 249 523 (M + H)⁺FAB 250 579 (M + H)⁺ESI 251 524 (M + H)⁺FAB 252 577 (M + H)⁺FAB 253 537 (M + H)⁺FAB 254 577 (M + H)⁺FAB 255 1.58-1.78 (2H, br), 1.93-2.06 (2H, br), 3.32-3.42 (3H, m), 3.48-3.58 (3H, m), 3.70-3.80 (1H, br), 3.85-3.95 (1H, br), 4.48-4.58 (1H, m), 4.92 (1H, br), 5.07 (2H, s), 6.95 (4H, s), 7.15 (1H, dt, J = 2.4, 8.8 Hz), 7.24-7.30 (2H, m), 7.41-7.47 (1H, m), 8.14 (1H, t, J = 2.0 Hz), 8.63 (1H, d, J = 2.4 Hz), 8.75 (1H, t J = 5.3 Hz), 8.93 (1H, d, J = 1.4 Hz), DMSO: 510 (M + H)⁺FAB

TABLE 51 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 256 586 (M + H)⁺FAB 257 549 (M + H)⁺FAB 258 1.13-1.33 (2H, br), 1.66 (2H, d, J = 12.7 Hz), 1.73-1.85 (1H, m), 2.57 (2H, d, J = 6.8 Hz), 2.86 (1H, t, J = 12.2 Hz), 3.02 (1H, t, J = 12.2 Hz), 4.03 (1H, d, J = 12.2 Hz), 4.20 (1H, d, J = 12.2 Hz), 7.18-7.23 (3H, m), 7.27-7.32 (2H, m), 7.48 (1H, s), 7.60 (1H, t, J = 7.8 Hz), 7.93 (2H, d, J = 7.3 Hz), 8.01 (1H, t, J = 2.4 Hz), 8.13 (1H, s), 8.23 (1H, s), 8.44 (1H, d, J = 2.4 Hz), 8.84 (1H, d, J = 2.0 Hz), DMSO: 416 (M + H)⁺FAB 259 374 (M + H)⁺FAB 260 1.60-1.75 (2H, m), 1.92-2.04 (2H, m), 3.30-3.91 (4H, m), 4.49-4.56 (1H, m), 5.07 (2H, s), 6.96 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.39-7.47 (2H, m), 7.92 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 2.0 Hz), DMSO: 438 (M + H)⁺FAB 261 550 (M + H)⁺FAB 262 1.58-1.75 (2H, m), 1.90-2.05 (2H, m), 3.30-3.57 (2H, m), 3.67-3.95 (2H, m), 4.13 (2H, s), 4.48-4.55 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.47 (1H, m), 7.61-7.64 (1H, m), 8.35-8.39 (1H, m), 8.40-8.44 (1H, m), DMSO: 510 (M⁺)FAB 263 1.58-1.74 (2H, m), 1.91-2.04 (2H, m), 2.50 (3H, s), 3.30-3.95 (4H, m), 4.48-4.58 (3H, m), 5.07 (2H, s), 5.40 (1H, t, J = 5.9 Hz), 6.95 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.47 (1H, m), 7.53-7.56 (1H, m), 8.28-8.31 (1H, m), 8.36-8.39 (1H, m), DMSO: 453 (M + H)⁺FAB 264 1.59-1.74 (2H, m), 1.96-2.03 (2H, m), 3.27-3.57 (2H, m), 3.70-3.65 (2H, m), 4.48-4.58 (3H, m), 5.08 (2H, s), 6.72 (1H, d, J = 16.1 Hz), 6.96 (4H, s), 7.12-7.18 (1H, m), 7.24-7.30 (2H, m), 7.40-7.47 (1H, m), 7.64 (1H, d, J = 16.1 Hz), 8.07 (1H, dd, J = 2.0 Hz, 2.0 Hz), 8.45 (1H, d, J = 2.5 Hz), 8.71 (1H, d, J = 1.4 Hz), 12.40-12.74 (1H, br), DMSO: 493 (M + H)⁺FAB 265 445 (M + H)⁺FAB 266 1.10-1.33 (2H, m), 1.45-1.61 (3H, m), 1.75-1.87 (2H, br), 2.64 (2H, t, J = 7.6 Hz), 2.81-3.10 (2H, br), 3.92-4.27 (2H, br), 7.14-7.32 (5H, m), 7.43-7.52 (1H, m), 7.60 (1H, d, J = 8.0 Hz), 7.90-7.98 (2H, m), 8.05-8.17 (2H, m), 8.21-8.27 (1H, m), 8.48 (1H, d, J = 2.4 Hz), 8.87 (1H, d, J = 2.4 Hz), DMSO 267 380 (M + H)⁺FAB 268 1.33-1.56 (2H, m), 1.77-1.88 (2H, m), 2.37-2.48 (1H, m), 2.93-3.04 (1H, m), 3.09-3.21 (1H, m), 3.98-4.12 (1H, m), 4.14-4.28 (1H, m), 6.31 (1H, dd, J = 16.1, 6.8 Hz), 6.45 (1H, d, J = 16.1 Hz), 7.18-7.24 (1H, m), 7.28-7.35 (2H, m), 7.38-7.48 (3H, m), 7.63 (1H, ddd, J = 8.3, 2.5, 1.5 Hz), 8.41-8.45 (2H, m), DMSO-d6: 309 (M + H)⁺FAB 269 1.33-1.56 (2H, m), 1.67-1.79 (2H, m), 2.73-2.88 (1H, m), 2.88-3.02 (1H, m), 2.88-3.02 (1H, m), 3.04-3.18 (1H, m), 3.95-4.07 (1H, m), 4.10-4.23 (1H, m), 5.54 (1H, dd, J = 11.8, 9.7 Hz), 6.42 (1H, d, J = 11.8 Hz), 7.23-7.34 (3H, m), 7.35-7.42 (2H, m), 7.44 (1H, dd, J = 8.3, 4.8 Hz), 7.63 (1H, ddd, J = 8.3, 2.4, 1.5 Hz), 8.40-8.45 (2H, m), DMSO: 309 (M + H)⁺FAB 270 1.08-1.30 (2H, m), 1.43-1.60 (3H, m), 1.73-1.82 (2H, br), 2.63 (2H, t, J = 7.8 Hz), 2.77-3.08 (2H, br), 3.92-4.20 (2H, br), 7.13-7.32 (5H, m), 8.04 (1H, dd, J = 2.0, 2.4 Hz), 8.45 (1H, d, J = 2.4 Hz), 8.58 (1H, d, J = 2.0 Hz), DMSO: 389 (M⁺)FAB

TABLE 52 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 271 0.78-0.94 (2H, m), 1.00-1.24 (10H, m), 1.37-1.50 (1H, m), 1.57-1.76 (7H, m), 2.80-2.92 (1H, br), 2.96-3.08 (1H, br), 3.93-4.05 (1H, br), 4.08-4.21 (1H, br), 7.68 (1H, dd, J = 4.8, 7.6 Hz), 7.93-8.00 (1H, m), 8.58 (1H, d, J = 7.6 Hz), 8.62-8.69 (1H, m), DMSO: 317 (M + H)⁺FAB 272 0.79-0.92 (2H, m), 1.04-1.29 (10H, m), 1.36-1.49 (1H, m), 1.57-1.76 (7H, m), 2.80-2.92 (1H, br), 2.95-3.08 (1H, br), 3.90 (3H, s), 3.92-4.05 (1H, br), 4.08-4.21 (1H, br), 8.09 (1H, dd, J = 2.0, 2.4 Hz), 8.68 (1H, d, J = 2.4 Hz), 8.93 (1H, d, J = 2.0 Hz), DMSO: 375 (M + H)⁺FAB 273 1.44-1.59 (2H, m), 1.77-1.88 (2H, m), 2.37-2.48 (1H, m), 2.93-3.07 (1H, m), 3.07-3.23 (1H, m), 3.98-4.14 (1H, m), 4.14-4.29 (1H, m), 6.31 (1H, dd, J = 16.1, 6.9 Hz), 6.45 (1H, d, J = 16.1 Hz), 7.17-7.25 (1H, m), 7.27-7.36 (2H, m), 7.38-7.44 (2H, m), 8.05-8.09 (1H, m), 8.67 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 1.5 Hz), 13.60 (1H, br s), DMSO: 353 (M + H)⁺FAB 274 1.10-1.30 (2H, m), 1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.63 (2H, t, J = 8.3 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.16-7.34 (4H, m), 8.04 (1H, dd, J = 1.5, 2.0 Hz), 8.64 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 1.9 Hz), 13.60 (1H, s), DMSO: 389 (M + H)⁺FAB 275 380 (M + H)⁺FAB 276 1.10-1.30 (2H, m), 1.44-1.60 (3H, m), 1.73-1.82 (2H, m), 2.60 (2H, t, J = 7.3 Hz), 2.80-3.10 (2H, m), 3.74 (3H, s), 3.95-4.24 (2H, m), 6.72-6.81 (3H, m), 7.19 (1H, t, J = 8.3 Hz), 8.04 (1H, t, J = 1.9 Hz), 8.64 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 1.5 Hz), 13.60 (1H, s)DMSO: 385 (M + H)⁺FAB 277 1.10-1.30 (2H, m), 1.44-1.60 (3H, m), 1.73-1.82 (2H, m), 2.60 (2H, t, J = 7.4 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 6.95-7.10 (3H, m), 7.29-7.36 (1H, m), 8.04 (1H, t, J = 2.0 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 1.9 Hz), 13.60 (1H, s), DMSO: 373 (M + H)⁺FAB 278 380 (M + H)⁺FAB 279 396 (M − H)⁻FAB 280 426 (M + H)⁺FAB 281 1.10-1.33 (2H, m), 1.46-1.59 (1H, m), 1.54-1.66 (2H, m), 1.75-1.87 (2H, m), 2.68 (2H, dd, J = 7.6, 7.6 Hz), 2.79-2.94 (1H, m), 2.95-3.10 (1H, m), 3.95-4.09 (1H, m), 4.11-4.25 (1H, m), 7.29-7.38 (3H, m), 7.41-7.49 (2H, m), 7.58 (2H, d, J = 8.3 Hz), 7.62-7.68 (2H, m), 7.78-7.81 (1H, m), 8.28 (1H, d, J = 2.5 Hz), 8.78 (1H, d, J = 1.4 Hz), DMSO: 431 (M + H)⁺FAB 282 1.07-1.33 (2H, m), 1.42-1.54 (1H, m), 1.47-1.59 (2H, m), 1.72-1.83 (2H, m), 2.62 (2H, dd, J = 7.6, 7.6 Hz), 2.78-2.93 (1H, m), 2.93-3.10 (1H, m), 3.92-4.08 (1H, m), 4.08-4.24 (1H, m), 7.05-7.13 (2H, m), 7.20-7.28 (2H, m), 8.04 (1H, dd, J = 2.5, 2.1 Hz), 8.64 (1H, d, J = 2.5 Hz), 8.92 (1H, d, J = 2.1 Hz), 13.62 (1H, br s), DMSO: 373 (M + H)⁺FAB 283 1.10-1.35 (2H, m), 1.46-1.62 (3H, m), 1.74-1.88 (2H, m), 2.74 (2H, dd, J = 7.8, 7.8 Hz), 2.80-2.96 (1H, m), 2.96-3.12 (1H, m), 3.94-4.08 (1H, m), 4.11-4.26 (1H, m), 7.18-7.32 (2H, m), 7.32-7.43 (2H, m), 8.05 (1H, dd, J = 2.1, 1.6 Hz), 8.65 (1H, d, J = 2.1 Hz), 8.91 (1H, d, J = 1.6 Hz), 13.62 (1H, br s), DMSO: 387 (M − H)⁻FAB 284 1.08-1.32 (2H, m), 1.41-1.55 (1H, m), 1.48-1.60 (2H, m), 1.71-1.83 (2H, m), 2.62 (2H, dd, J = 7.8, 7.8 Hz), 2.78-2.93 (1H, m), 2.93-3.09 (1H, m), 3.94-4.08 (1H, m), 4.10-4.23 (1H, m), 7.25 (2H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.0 Hz), 8.04 (1H, dd, J = 2.2, 1.6 Hz), 8.64 (1H, d, J = 2.2 Hz), 8.91 (1H, d, J = 1.6 Hz), 13.61 (1H, br s), DMSO: 389 (M + H)⁺FAB 285 1.06-1.32 (2H, m), 1.40-1.54 (1H, m), 1.47-1.60 (2H, m), 1.70-1.84 (2H, m), 2.61 (2H, dd, J = 7.6, 7.6 Hz), 2.79-2.94 (1H, m), 2.94-3.09 (1H, m), 3.92-4.08 (1H, m), 4.08-4.25 (1H, m), 7.19 (2H, d, J = 8.4 Hz), 7.46 (2H, d, J = 8.4 Hz), 8.04 (1H, dd, J = 2.4, 1.2 Hz), 8.64 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 1.2 Hz), 13.60 (1H, br s), DMSO: 431 (M − H)⁻FAB 286 1.08-1.32 (2H, m), 1.42-1.58 (3H, m), 1.70-1.84 (2H, m), 2.56 (2H, dd, J = 7.4, 7.4 Hz), 2.78-2.93 (1H, m), 2.93-3.07 (1H, m), 3.72 (3H, s), 3.94-4.08 (1H, m), 4.08-4.23 (1H, m), 6.84 (2H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.0 Hz), 8.04 (1H, dd, J = 2.8, 1.6 Hz), 8.64 (1H, d, J = 2.8 Hz), 8.91 (1H, d, J = 1.6 Hz), 13.60 (1H, br s), DMSO: 385 (M + H)⁺FAB

TABLE 53 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 287 1.01-1.74 (11H, m), 2.58 (2H, t, J = 7.2 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.14-7.31 (5H, m), 8.04 (1H, t, J = 2.4 Hz), 8.64 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 1.6 Hz), 13.60 (1H, s), DMSO: 383 (M + H)⁺FAB 288 1.08-1.34 (2H, m), 1.44-1.60 (3H, m), 1.73-1.86 (2H, m), 2.66 (2H, dd, J = 7.4, 7.4 Hz), 2.78-2.95 (1H, m), 2.95-3.12 (1H, m), 3.93-4.09 (1H, m), 4.10-4.26 (1H, m), 7.08-7.18 (2H, m), 7.20-7.27 (1H, m), 7.27-7.36 (1H, m), 8.05 (1H, dd, J = 2.4, 1.6 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 1.6 Hz), 13.60 (1H, br s), DMSO: 373 (M + H)⁺FAB 289 0.79-0.93 (2H, m), 1.00-1.28 (10H, m), 1.35-1.48 (1H, m), 1.57-1.76 (7H, m), 2.80-3.08 (2H, br), 3.96-4.22 (2H, br), 8.02-8.05 (1H, m), 8.62-8.66 (1H, m), 8.89-8.93 (1H, m), 13.53-13.64 (1H, br), DMSO: 361 (M + H)⁺FAB 290 1.13-1.32 (2H, m), 1.46-1.59 (1H, m), 1.54-1.62 (2H, m), 1.75-1.87 (2H, m), 2.69 (2H, dd, J = 7.8, 7.8 Hz), 2.81-2.94 (1H, m), 2.94-3.10 (1H, m), 3.94-4.10 (1H, m), 4.10-4.27 (1H, m), 7.29-7.38 (3H, m), 7.86 (1H, ddd, J = 7.4, 7.4, 1.6 Hz), 7.93 (1H, d, J = 8.0 Hz), 8.01 (2H, d, J = 8.0 Hz), 8.05 (1H, dd, J = 2.8, 1.6 Hz), 8.62-8.68 (2H, m), 8.92 (1H, d, J = 1.6 Hz), 13.60 (1H, br s), DMSO: 432 (M + H)⁺ESI 291 1.08-1.32 (2H, m), 1.44-1.61 (3H, m), 1.77-1.83 (2H, br), 2.63 (2H, t, J = 7.6 Hz), 2.79-3.08 (2H, br), 3.95-4.23 (2H, br), 6.73 (1H, d, J = 16.0 Hz), 7.14-7.22 (3H, m), 7.25-7.32 (2H, m), 7.64 (1H, d, J = 16.0 Hz), 8.02-8.06 (1H, m), 8.40-8.44 (1H, m), 8.68-8.73 (1H, m), 12.55-12.63 (1H, br), DMSO: 381 (M + H)⁺FAB 292 1.10-1.32 (2H, m), 1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.63 (2H, t, J = 8.4 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.20-7.28 (2H, m), 7.36-7.40 (1H, m), 7.44 (1H, br), 8.04 (1H, t, J = 2.0 Hz), 8.64 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 1.6 Hz), 13.60 (1H, s), DMSO: 435, 433 (M + H)⁺ESI 293 1.10-1.32 (2H, m), 1.45-1.67 (3H, m), 1.75-1.87 (2H, m), 2.71 (2H, t, J = 7.6 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.22 (1H, d, J = 7.2 Hz), 7.33-7.52 (6H, m), 7.64-7.68 (1H, m), 8.04 (1H, dd, J = 1.2, 2.4 Hz), 8.64 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 2.0 Hz), 13.60 (1H, s), DMSO: 431 (M + H)⁺ESI 294 1.10-1.32 (2H, m), 1.45-1.67 (3H, m), 1.75-1.87 (2H, m), 2.71 (2H, t, J = 7.6 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.29 (1H, d, J = 7.6 Hz), 7.41 (1H, t, J = 8.0 Hz), 7.55 (1H, d, J = 7.6 Hz), 7.62 (1H, s), 7.67 (1H, t, J = 8.0 Hz), 7.82 (1H, d, J = 8.0 Hz), 8.00-8.08 (2H, m), 8.16 (1H, s), 8.65 (1H, br), 8.91 (1H, br), 13.60 (1H, s), DMSO: 456 (M + H)⁺FAB 295 1.07-1.34 (2H, m), 1.41-1.58 (1H, m), 1.50-1.63 (2H, m), 1.70-1.85 (2H, m), 2.65 (2H, dd, J = 7.6, 7.6 Hz), 2.78-2.94 (1H, m), 2.93-3.21 (1H, m), 3.92-4.09 (1H, m), 4.06-4.26 (1H, m), 7.26 (2H, d, J = 6.0 Hz), 8.04 (1H, dd, J = 2.8, 2.0 Hz), 8.45 (2H, br d, J = 4.4 Hz), 8.64 (1H, d, J = 2.8 Hz), 8.91 (1H, d, J = 2.0 Hz), DMSO: 356 (M + H)⁺FAB 296 1.08-1.35 (2H, m), 1.43-1.58 (1H, m), 1.50-1.63 (2H, m), 1.71-1.86 (2H, m), 2.65 (2H, dd, J = 7.2, 7.2 Hz), 2.77-2.96 (1H, m), 2.90-3.11 (1H, m), 3.90-4.08 (1H, m), 4.10-4.26 (1H, m), 7.31 (1H, dd, J = 8.0, 4.8 Hz), 7.65 (1H, d, J = 8.0 Hz), 8.04 (1H, dd, J = 2.4, 2.0 Hz), 8.40 (1H, br d, J = 3.2 Hz), 8.46 (1H, br s), 8.65 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 2.0 Hz), DMSO: 354 (M − H)⁻FAB 297 1.08-1.35 (2H, m), 1.43-1.60 (1H, m), 1.60-1.72 (2H, m), 1.74-1.85 (2H, m), 2.78 (2H, dd, J = 7.2, 7.2 Hz), 2.81-2.93 (1H, m), 2.94-3.08 (1H, m), 3.95-4.07 (1H, m), 4.11-4.24 (1H, m), 7.16-7.22 (1H, m), 7.27 (1H, d, J = 8.0 Hz), 7.69 (1H, ddd, J = 8.0, 8.0, 2.0 Hz), 8.04 (1H, dd, J = 2.4, 2.0 Hz), 8.48 (1H, d, J = 4.4 Hz), 8.64 (1H, d, J = 2.4 Hz), 8.91 (1H, d, J = 2.0 Hz), DMSO: 354 (M − H)⁻FAB 298 1.10-1.32 (2H, m), 1.45-1.67 (3H, m), 1.75-1.87 (2H, m), 2.69-2.75 (2H, m), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.27-7.46 (3H, m), 7.80-7.99 (5H, m), 8.30 (1H, d, J = 2.8 Hz), 8.66 (1H, d, J = 4.4 Hz), 8.80 (1H, d, J = 1.6 Hz), DMSO: 432 (M + H)⁺FAB

TABLE 54 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 299 1.10-1.36 (2H, m), 1.45-1.60 (1H, m), 1.54-1.66 (2H, m), 1.74-1.87 (2H, m), 2.67 (2H, dd, J = 7.2, 7.2 Hz), 2.80-2.95 (1H, m), 2.95-3.10 (1H, m), 3.92-4.10 (1H, m), 4.10-4.25 (1H, m), 7.26 (2H, d, J = 8.8 Hz), 7.30 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.68 (2H, dd, J = 8.8, 5.2 Hz), 8.05 (1H, dd, J = 3.2, 1.6 Hz), 8.65 (1H, d, J = 3.2 Hz), 8.92 (1H, d, J = 1.6 Hz), 13.60 (1H, br s), DMSO: 449 (M + H)⁺FAB 300 1.11-1.36 (2H, m), 1.46-1.59 (1H, m), 1.54-1.64 (2H, m), 1.74-1.86 (2H, m), 2.66 (2H, dd, J = 7.6, 7.6 Hz), 2.81-2.95 (1H, m), 2.95-3.10 (1H, m), 3.79 (3H, s), 3.95-4.07 (1H, m), 4.12-4.25 (1H, m), 7.01 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz), 7.58 (2H, d, J = 8.8 Hz), 8.05 (1H, dd, J = 2.8, 2.0 Hz), 8.65 (1H, d, J = 2.8 Hz), 8.92 (1H, d, J = 2.0 Hz), 13.60 (1H, br s), DMSO: 461 (M + H)⁺FAB 301 1.10-1.36 (2H, m), 1.45-1.59 (1H, m), 1.55-1.66 (2H, m), 1.75-1.87 (2H, m), 2.69 (2H, dd, J = 7.2, 7.2 Hz), 2.80-2.94 (1H, m), 2.96-3.12 (1H, m), 3.93-4.10 (1H, m), 4.10-4.27 (1H, m), 7.36 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz), 8.05 (1H, dd, J = 2.4, 1.6 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 1.6 Hz), 13.61 (1H, br s), DMSO: 456 (M + H)⁺FAB 302 1.10-1.36 (2H, m), 1.45-1.58 (1H, m), 1.55-1.65 (2H, m), 1.71-1.88 (2H, m), 2.68 (2H, dd, J = 7.6, 7.6 Hz), 2.78-2.95 (1H, m), 2.95-3.12 (1H, m), 3.92-4.10 (1H, m), 4.10-4.26 (1H, m), 7.10-7.22 (1H, m), 7.32 (2H, d, J = 8.0 Hz), 7.42-7.54 (3H, m), 7.63 (2H, d, J = 8.0 Hz), 8.05 (1H, dd, J = 2.4, 2.0 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 2.0 Hz), 13.61 (1H, br s), DMSO: 449 (M + H)⁺FAB 303 1.11-1.35 (2H, m), 1.46-1.58 (1H, m), 1.54-1.64 (2H, m), 1.75-1.86 (2H, m), 2.67 (2H, dd, J = 7.6, 7.6 Hz), 2.80-2.95 (1H, m), 2.95-3.12 (1H, m), 3.82 (3H, s), 3.94-4.10 (1H, m), 4.10-4.25 (1H, m), 6.91 (1H, ddd, J = 8.4, 2.4, 0.8 Hz), 7.14-7.18 (1H, m), 7.18-7.23 (1H, m), 7.30 (2H, d, J = 8.4 Hz), 7.36 (1H, dd, J = 8.0, 8.0 Hz), 7.59 (2H, d, J = 8.4 Hz), 8.05 (1H, dd, J = 2.4, 2.0 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 2.0 Hz), 13.60 (1H, br s), DMSO: 459 (M − H)⁻ESI 304 1.10-1.36 (2H, m), 1.47-1.58 (1H, m), 1.55-1.66 (2H, m), 1.74-1.88 (2H, m), 2.87 (2H, dd, J = 7.6, 7.6 Hz), 2.82-2.96 (1H, m), 2.96-3.13 (1H, m), 3.95-4.10 (1H, m), 4.10-4.26 (1H, m), 7.24-7.32 (2H, m), 7.33 (2H, d, J = 8.4 Hz), 7.36-7.44 (1H, m), 7.44-7.50 (2H, m), 7.48-7.55 (1H, m), 8.05 (1H, dd, J = 2.4, 1.6 Hz), 8.65 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 1.6 Hz), 13.61 (1H, br s), DMSO: 449 (M + H)⁺FAB 305 480 (M + H)⁺FAB 306 488 (M + Na)⁺ESI 307 490 (M + Na)⁺ESI 308 1.12-1.29 (2H, m), 1.50-1.63 (9H, m), 1.78-1.81 (2H, br), 2.64-2.69 (2H, m), 2.86 (1H, br), 3.02 (1H, br), 3.23-3.38 (2H, m), 3.51-3.64 (2H, m), 4.01 (1H, m), 4.17 (1H, m), 7.25-7.31 (4H, m), 7.80 (1H, m), 8.28 (1H, m), 8.80 (1H, m), DMSO: 464 (M − H)⁻FAB 309 1.15-1.28 (2H, m), 1.47-1.60 (3H, m), 1.78-1.81 (2H, br), 2.65-2.69 (2H, br), 2.86 (1H, m), 3.02 (1H, m), 3.40-3.63 (8H, br), 4.01 (1H, m), 4.18 (1H, m), 7.28-7.34 (4H, m), 7.80 (1H, m), 8.28 (1H, m), 8.80 (1H, m), DMSO: 468 (M + H)⁺FAB 310 452 (M + H)⁺FAB 311 544 (M + H)⁺ESI 312 454 (M + H)⁺ESI 313 1.10-1.80 (16H, m), 2.27 (3H, s), 2.65-2.74 (2H, m), 2.80-3.10 (2H, m), 3.95-4.32 (4H, m), 6.42 (1H, d, J = 7.6 Hz), 6.56 (1H, d, J = 8.8 Hz), 7.36 (1H, t, J = 8.0 Hz), 7.80 (1H, br), 8.27 (1H, d, J = 3.2 Hz), 8.79 (1H, br), DMSO: 467 (M + H)⁺FAB 314 1.07-1.21 (2H, m), 1.27-1.51 (10H, m), 1.73-1.77 (2H, br), 1.81-1.84 (2H, br) 2.83-2.89 (3H, br), 3.04 (1H, br), 3.72-3.76 (2H, br), 4.02 (1H, br), 4.18 (1H, br), 7.33 (1H, m), 7.58 (1H, m), 7.68 (1H, m), 7.80 (1H, m), 7.86 (1H, m), 8.04 (1H, m), 8.08 (1H, m), 8.28 (1H, m), 8.79 (1H, m), DMSO: 503 (M + H)⁺FAB

TABLE 55 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 315 1.00-1.82 (16H, m), 2.77-3.08 (4H, m), 3.95-4.23 (2H, m), 4.53 (2H, d, J = 12.0 Hz), 7.10-7.23 (2H, m), 7.42-7.58 (2H, m), 7.66 (1H, d, J = 7.5 Hz), 7.81 (1H, s), 7.99 (1H, d, J = 8.5 Hz), 8.29 (1H, d, J = 2.2 Hz), 8.80 (1H, s), DMSO: 503 (M + H)⁺FAB 316 1.08-1.23 (2H, m), 1.26-1.32 (2H, m), 1.47-1.57 (3H, m), 1.73-1.77 (2H, m), 2.37-2.41 (2H, m) 2.61-2.67 (4H, br), 2.87 (1H, m), 2.03 (1H, m), 3.27-3.33 (4H, br), 4.02 (1H, br), 4.18 (1H, br), 7.37 (1H, m), 7.59 (1H, m), 7.70 (1H, m), 7.81 (1H, m), 7.87 (1H, m), 8.06-8.11 (2H, m), 8.29 (1H, m), 8.80 (1H, m), DMSO: 526 (M + Na)⁺ESI 317 1.07-1.21 (2H, m), 1.27-1.51 (10H, m), 1.73-1.77 (2H, br), 1.82-1.85 (2H, br) 2.67-2.73 (2H, br), 2.87 (1H, m), 3.02 (1H, br), 3.28-3.39 (2H, br), 4.02 (1H, br), 4.18 (1H, br), 7.09 (1H, m), 7.41 (1H, m), 7.46-7.52 (2H, m), 7.55 (1H, m), 7.82 (1H, m), 7.86 (1H, m), 8.08 (1H, m), 8.29 (1H, m), 8.80 (1H, m), DMSO: 524 (M + Na)⁺FAB 318 1.10-1.30 (2H, m), 1.44-1.62 (3H, m), 1.75-1.83 (2H, m), 2.70 (2H, t, J = 7.3 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.47-7.74 (5H, m), 8.02 (1H, t, J = 2.5 Hz), 8.17 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 379 (M + H)⁺FAB 319 1.10-1.30 (2H, m), 1.45-1.59 (3H, m), 1.80 (2H, d, J = 12.2 Hz), 2.63 (2H, t, J = 7.4 Hz), 2.88 (1H, t, J = 12.2 Hz), 3.03 (1H, t, J = 12.2 Hz), 3.31-3.38 (2H, m), 3.50-3.55 (2H, m), 4.02 (1H, d, J = 12.2 Hz), 4.18 (1H, d, J = 12.2 Hz), 7.15-7.31 (5H, m), 8.01 (1H, t, J = 2.4 Hz), 8.55 (1H, s), 8.69 (1H, t, J = 5.6 Hz), 8.88 (1H, s), DMSO: 398 (M + H)⁺FAB 320 1.10-1.30 (2H, m), 1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.63 (2H, t, J = 7.4 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.15-7.31 (5H, m), 7.67 (1H, s), 8.01 (1H, t, J = 1.9 Hz), 8.17 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 354 (M + H)⁺FAB 321 1.10-1.30 (2H, m), 1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.60 (2H, t, J = 7.3 Hz), 2.80-3.10 (2H, m), 3.74 (3H, s), 3.95-4.24 (2H, m), 6.70-6.84 (3H, m), 7.13-7.24 (1H, m), 7.66 (1H, s), 8.01 (1H, br), 8.18 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, br), DMSO: 384 (M + H)⁺FAB 322 1.10-1.30 (2H, m), 1.44-1.60 (3H, m), 1.75-1.83 (2H, m), 2.65 (2H, t, J = 7.3 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 6.96-7.10 (3H, m), 7.29-7.36 (1H, m), 7.66 (1H, s), 8.01 (1H, t, J = 2.5 Hz), 8.17 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.9 Hz), DMSO: 372 (M + H)⁺FAB 323 1.10-1.34 (2H, m), 1.50-1.64 (3H, m), 1.75-1.88 (2H, m), 2.80-3.10 (4H, m), 3.95-4.24 (2H, m), 7.41 (1H, dt, J = 1.0, 7.4 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.62-7.70 (2H, m), 7.79 (1H, dd, J = 1.5, 7.8 Hz), 8.02 (1H, t, J = 2.0 Hz), 8.17 (1H, s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 379 (M + H)⁺FAB 324 1.10-1.34 (2H, m), 1.45-1.64 (3H, m), 1.75-1.88 (2H, m), 2.66 (2H, t, J = 7.8 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.26-7.40 (3H, m), 7.64-7.75 (3H, m), 7.92 (1H, s), 8.01 (1H, br), 8.17 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.4 Hz), DMSO: 397 (M + H)⁺FAB 325 1.10-1.34 (2H, m), 1.45-1.64 (3H, m), 1.75-1.85 (2H, m), 2.66 (2H, t, J = 7.3 Hz), 2.80-3.10 (8H, m), 3.95-4.24 (2H, m), 7.16-7.37 (4H, m), 7.66 (1H, s), 8.01 (1H, br), 8.17 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.4 Hz), DMSO: 425 (M + H)⁺FAB 326 0.79-0.93 (2H, m), 1.02-1.30 (10H, m), 1.37-1.49 (1H, m) 1.57-1.77 (7H, m), 2.81-2.92 (1H, br), 2.96-3.08 (1H, br), 3.94-4.05 (1H, br), 4.10-4.21 (1H, br), 7.63-7.70 (1H, br), 8.00 (1H, dd, J = 3.0 Hz, 2.4 Hz), 8.13-8.21 (1H, m), 8.55 (1H, d, J = 3.0 Hz),, 8.88 (1H, d, J = 2.4 Hz), DMSO: 360 (M + H)⁺FAB 327 1.10-1.30 (2H, m), 1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.63 (2H, t, J = 7.2 Hz), 2.80-3.10 (2H, m), 3.30-3.38 (2H, m), 3.49-3.55 (2H, m), 3.95-4.24 (2H, m), 7.16-7.34 (4H, m), 8.02 (1H, t, J = 2.4 Hz), 8.55 (1H, br), 8.69 (1H, t, J = 5.6 Hz), 8.87 (1H, s), DMSO: 432 (M + H)⁺FAB

TABLE 56 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 328 1.10-1.30 (2H, m), 1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.60 (2H, t, J = 7.6 Hz), 2.80-3.10 (2H, m), 3.30-3.38 (2H, m), 3.49-3.55 (2H, m), 3.74 (3H, s), 3.95-4.24 (2H, m), 6.71-6.82 (3H, m), 7.19 (1H, t, J = 7.2 Hz), 8.01 (1H, br), 8.55 (1H, br), 8.68 (1H, t, J = 6.0 Hz), 8.87 (1H, br), DMSO: 428 (M + H)⁺FAB 329 1.10-1.30 (2H, m), 1.45-1.60 (3H, m), 1.75-1.85 (2H, m), 2.65 (2H, t, J = 8.4 Hz), 2.80-3.10 (2H, m), 3.30-3.38 (2H, m), 3.49-3.55 (2H, m), 3.95-4.24 (2H, m), 7.05-7.10 (3H, m), 7.30-7.35 (1H, m), 8.00 (1H, t, J = 2.4 Hz), 8.55 (1H, br), 8.68 (1H, t, J = 5.6 Hz), 8.87 (1H, br), DMSO: 416 (M + H)⁺FAB 330 1.10-1.30 (2H, m), 1.45-1.62 (3H, m), 1.75-1.85 (2H, m), 2.70 (2H, t, J = 7.2 Hz), 2.80-3.10 (2H, m), 3.30-3.38 (2H, m), 3.49-3.55 (2H, m), 3.95-4.24 (2H, m), 7.50 (1H, t, J = 8.0 Hz), 7.56-7.74 (3H, m), 8.02 (1H, t, J = 2.0 Hz), 8.55 (1H, d, J = 2.0 Hz), 8.69 (1H, t, J = 6.0 Hz), 8.87 (1H, br), DMSO: 423 (M + H)⁺FAB 331 1.10-1.34 (2H, m), 1.50-1.64 (3H, m), 1.75-1.89 (2H, m), 2.84 (2H, t, J = 8.0 Hz), 2.84-3.11 (2H, m), 3.31-3.38 (2H, m), 3.49-3.55 (2H, m), 3.95-4.25 (2H, m), 7.40 (1H, dt, J = 0.8, 7.6 Hz), 7.52 (1H, d, J = 7.2 Hz), 7.65 (1H, dt, J = 1.6, 7.6 Hz), 7.79 (1H, dd, J = 1.2, 8.0 Hz), 8.04 (1H, t, J = 2.0 Hz), 8.55 (1H, d, J = 2.4 Hz), 8.69 (1H, t, J = 5.6 Hz), 8.87 (1H, d, J = 1.6 Hz), DMSO: 423 (M + H)⁺FAB 332 462 (M + H)⁺FAB 333 1.10-1.30 (2H, m), 1.45-1.60 (3H, m), 1.80 (2H, d, J = 12.0 Hz), 2.37 (2H, t, J = 7.2 Hz), 2.63 (2H, t, J = 7.2 Hz), 2.87 (1H, t, J = 12.2 Hz), 3.03 (1H, t, J = 12.2 Hz), 3.41-3.49 (2H, m), 4.01 (1H, d, J = 12.2 Hz), 4.18 (1H, d, J = 12.2 Hz), 6.83 (1H, s), 7.15-7.31 (5H, m), 7.36 (1H, s), 7.99 (1H, t, J = 2.4 Hz), 8.55 (1H, d, J = 3.2 Hz), 8.76 (1H, t, J = 5.6 Hz), 8.85 (1H, t, J = 2.0 Hz), DMSO: 425 (M + H)⁺FAB 334 1.08-1.32 (2H, m), 1.45-1.60 (3H, m), 1.74-1.86 (2H, m), 2.66 (2H, dd, J = 7.2, 7.2 Hz), 2.80-2.95 (1H, m), 2.95-3.11 (1H, m), 3.95-4.08 (1H, m), 4.11-4.25 (1H, m), 7.09-7.17 (2H, m), 7.20-7.28 (1H, m), 7.28-7.36 (1H, m), 7.67 (1H, br s), 8.02 (1H, dd, J = 2.4, 2.0 Hz), 8.18 (1H, br s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 372 (M + H)⁺FAB 335 1.08-1.32 (2H, m), 1.44-1.61 (3H, m), 1.77-1.83 (2H, br), 2.63 (2H, t, J = 7.6 Hz), 2.79-3.08 (2H, br), 3.95-4.23 (2H, br), 6.73 (1H, d, J = 16.0 Hz), 7.14-7.22 (3H, m), 7.25-7.32 (2H, m), 7.64 (1H, d, J = 16.0 Hz), 8.02-8.06 (1H, m), 8.40-8.44 (1H, m), 8.68-8.73 (1H, m), 12.55-12.63 (1H, br), DMSO: 380 (M + H)⁺FAB 336 1.09-1.31 (2H, m), 1.43-1.56 (1H, m), 1.53-1.64 (2H, m), 1.71-1.86 (2H, m), 2.67 (2H, dd, J = 8.0, 8.0 Hz), 2.79-2.96 (1H, m), 2.92-3.11 (1H, m), 3.93-4.10 (1H, m), 4.08-4.24 (1H, m), 7.31 (2H, d, J = 5.2 Hz), 7.67 (1H, s), 8.01 (1H, dd, J = 2.4, 1.6 Hz), 8.19 (1H, s), 8.49 (2H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.6 Hz), DMSO: 355 (M + H)⁺ESI 337 1.08-1.32 (2H, m), 1.43-1.57 (1H, m), 1.52-1.63 (2H, m), 1.72-1.86 (2H, m), 2.66 (2H, dd, J = 7.2, 7.2 Hz), 2.80-2.95 (1H, m), 2.95-3.11 (1H, m), 3.93-4.08 (1H, m), 4.10-4.25 (1H, m), 7.33 (1H, dd, J = 7.6, 4.8 Hz), 7.62-7.72 (2H, m), 8.01 (1H, dd, J = 2.4, 1.6 Hz), 8.19 (1H, br s), 8.41 (1H, br s), 8.47 (1H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.6 Hz), DMSO: 355 (M + H)⁺ESI 338 1.10-1.33 (2H, m), 1.45-1.59 (1H, m), 1.54-1.65 (2H, m), 1.75-1.87 (2H, m), 2.67 (2H, dd, J = 7.6, 7.6 Hz), 2.81-2.95 (1H, m), 2.96-3.10 (1H, m), 3.92-4.08 (1H, m), 4.11-4.25 (1H, m), 7.27 (2H, t, J = 8.8 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.63-7.72 (3H, m), 8.02 (1H, dd, J = 2.4, 2.0 Hz), 8.19 (1H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 448 (M + H)⁺FAB 339 1.10-1.33 (2H, m), 1.47-1.63 (1H, m), 1.53-1.65 (2H, m), 1.76-1.88 (2H, m), 2.66 (2H, dd, J = 7.2, 7.2 Hz), 2.80-2.96 (1H, m), 2.96-3.11 (1H, m), 3.79 (3H, s), 3.96-4.07 (1H, m), 4.12-4.25 (1H, m), 7.01 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.53 (2H, d, J = 8.4 Hz), 7.58 (2H, d, J = 8.4 Hz), 7.67 (1H, br s), 8.02 (1H, dd, J = 2.4, 2.0 Hz), 8.19 (1H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 458 (M + H)⁺FAB

TABLE 57 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 340 1.10-1.32 (2H, m), 1.45-1.67 (3H, m), 1.75-1.87 (2H, m), 2.71 (2H, t, J = 8.0 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.23 (1H, d, J = 7.2 Hz), 7.33-7.52 (6H, m), 7.64-7.71 (2H, m), 8.02 (1H, t, J = 2.0 Hz), 8.19 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.6 Hz), DMSO: 430 (M + H)⁺FAB 341 1.10-1.32 (2H, m), 1.45-1.67 (3H, m), 1.75-1.87 (2H, m), 2.71 (2H, t, J = 7.6 Hz), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.29 (1H, d, J = 7.6 Hz), 7.41 (1H, t, J = 7.6 Hz), 7.55 (1H, d, J = 7.2 Hz), 7.60-7.73 (3H, m), 7.82 (1H, d, J = 7.2 Hz), 8.00-8.08 (2H, m), 8.16 (1H, s), 8.20 (1H, s), 8.65 (1H, br), 8.91 (1H, br), DMSO: 455 (M + H)⁺FAB 342 1.06-1.30 (2H, m), 1.43-1.56 (1H, m), 1.51-1.61 (2H, m), 1.69 (2H, q, J = 6.4 Hz), 1.74-1.85 (2H, m), 2.63 (2H, dd, J = 7.6, 7.6 Hz), 2.80-2.94 (1H, m), 2.94-3.10 (2H, m), 3.33 (2H, td, J = 6.4, 6.4 Hz), 3.47 (2H, t, J = 6.4 Hz), 3.93-4.09 (1H, m), 4.09-4.24 (1H, m), 7.13-7.24 (3H, m), 7.24-7.31 (2H, m), 7.99 (1H, dd, J = 2.4, 1.6 Hz), 8.54 (1H, d, J = 2.4 Hz), 8.67 (1H, br t, J = 5.2 Hz), 8.85 (1H, d, J = 1.6 Hz), DMSO: 412 (M + H)⁺FAB 343 1.08-1.31 (2H, m), 1.44-1.56 (1H, m), 1.52-1.61 (2H, m), 1.74-1.86 (2H, m), 1.82-1.93 (2H, m), 2.63 (2H, dd, J = 7.2, 7.2 Hz), 2.72 (6H, s), 2.80-2.93 (1H, m), 2.98-3.09 (3H, m), 3.34 (2H, td, J = 6.4, 6.4 Hz), 3.94-4.07 (1H, m), 4.10-4.24 (1H, m), 7.13-7.24 (3H, m), 7.24-7.32 (2H, m), 8.00 (1H, dd, J = 2.4, 1.6 Hz), 8.57 (1H, d, J = 2.4 Hz), 8.85 (1H, br t, J = 5.6 Hz), 8.88 (1H, d, J = 1.6 Hz), DMSO: 439 (M + H)⁺FAB 344 1.09-1.34 (2H, m), 1.45-1.60 (1H, m), 1.55-1.66 (2H, m), 1.75-1.87 (2H, m), 2.70 (2H, dd, J = 7.6, 7.6 Hz), 2.80-2.96 (1H, m), 2.96-3.11 (1H, m), 3.94-4.09 (1H, m), 4.10-4.26 (1H, m), 7.37 (2H, d, J = 8.4 Hz), 7.68 (1H, br s), 7.69 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.4 Hz), 7.91 (2H, d, J = 8.4 Hz), 8.02 (1H, dd, J = 2.4, 2.0 Hz), 8.19 (1H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 455 (M + H)⁺FAB 345 1.10-1.34 (2H, m), 1.46-1.60 (1H, m), 1.54-1.66 (2H, m), 1.75-1.89 (2H, m), 2.68 (2H, dd, J = 7.6, 7.6 Hz), 2.80-2.96 (1H, m), 2.96-3.12 (1H, m), 3.95-4.09 (1H, m), 4.11-4.26 (1H, m), 7.13-7.21 (1H, m), 7.33 (2H, d, J = 8.0 Hz), 7.45-7.52 (3H, m), 7.63 (2H, d, J = 8.0 Hz), 7.67 (1H, br s), 8.02 (1H, dd, J = 2.4, 2.0 Hz), 8.19 (1H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 448 (M + H)⁺FAB 346 1.10-1.35 (2H, m), 1.48-1.61 (1H, m), 1.56-1.66 (2H, m), 1.76-1.90 (2H, m), 2.69 (2H, dd, J = 8.0, 8.0 Hz), 2.81-2.97 (1H, m), 2.97-3.13 (1H, m), 3.95-4.10 (1H, m), 4.10-4.26 (1H, m), 7.25-7.32 (2H, m), 7.33 (2H, d, J = 8.0 Hz), 7.36-7.44 (1H, m), 7.44-7.50 (2H, m), 7.48-7.56 (1H, m), 7.67 (1H, br s), 8.02 (1H, dd, J = 2.8, 2.0 Hz), 8.19 (1H, br s), 8.56 (1H, d, J = 2.8 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 448 (M + H)⁺FAB 347 1.08-1.31 (2H, m), 1.43-1.55 (1H, m), 1.50-1.61 (2H, m), 1.72-1.85 (2H, m), 2.63 (2H, dd, J = 7.8, 7.8 Hz), 2.80-2.93 (1H, m), 2.90 (2H, t, J = 6.8 Hz), 2.96-3.09 (1H, m), 3.56 (2H, td, J = 6.8, 6.8 Hz), 3.93-4.08 (1H, m), 4.08-4.23 (1H, m), 7.14-7.24 (3H, m), 7.24-7.31 (2H, m), 7.33 (2H, d, J = 5.6 Hz), 7.95 (1H, dd, J = 2.8, 1.6 Hz), 8.50 (2H, br s), 8.55 (1H, d, J = 2.8 Hz), 8.81 (1H, d, J = 1.6 Hz), 8.81 (1H, t, J = 6.0 Hz), DMSO: 459 (M + H)⁺FAB 348 1.08-1.31 (2H, m), 1.43-1.57 (1H, m), 1.50-1.62 (2H, m), 1.73-1.86 (2H, m), 2.63 (2H, dd, J = 7.8, 7.8 Hz), 2.80-2.93 (1H, m), 2.89 (2H, t, J = 6.8 Hz), 2.96-3.09 (1H, m), 3.54 (2H, td, J = 6.8, 6.8 Hz), 3.94-4.09 (1H, m), 4.09-4.25 (1H, m), 7.13-7.25 (3H, m), 7.25-7.32 (2H, m), 7.35 (1H, dd, J = 7.6, 4.8 Hz), 7.71 (1H, d, J = 7.6 Hz), 7.92-7.97 (1H, m), 8.44 (1H, br s), 8.49 (1H, br s), 8.52-8.59 (1H, m), 8.77-8.85 (2H, m), DMSO: 459 (M + H)⁺FAB 349 1.10-1.32 (2H, m), 1.45-1.67 (3H, m), 1.75-1.87 (2H, m), 2.69-2.78 (2H, m), 2.80-3.10 (2H, m), 3.95-4.24 (2H, m), 7.27-7.46 (3H, m), 7.66 (1H, s), 7.83-8.03 (5H, m), 8.18 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.66 (1H, br), 8.89 (1H, d, J = 1.2 Hz), DMSO: 431 (M + H)⁺FAB 350 425 (M + H)⁺FAB 351 1.05-1.85 (17H, m), 2.67 (2H, t, J = 7.6 Hz), 2.80-3.10 (2H, m), 3.70-3.80 (1H, m), 3.95-4.24 (2H, m), 7.33-7.37 (2H, m), 7.62-7.70 (3H, m), 8.01 (1H, t, J = 2.0 Hz), 8.13 (1H, d, J = 7.6 Hz), 8.17 (1H, s), 8.55 (1H, d, J = 2.8 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 479 (M + H)⁺FAB

TABLE 58 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 352 411 (M + H)⁺FAB 353 1.08-1.32 (2H, m), 1.43-1.58 (1H, m), 1.52-1.64 (2H, m), 1.72-1.87 (2H, m), 2.68 (2H, dd, J = 7.8, 7.8 Hz), 2.78-2.95 (1H, m), 2.97-3.12 (1H, m), 3.93-4.09 (1H, m), 4.10-4.25 (1H, m), 7.26 (1H, br s), 7.29 (2H, d, J = 8.0 Hz), 7.67 (1H, br s), 7.79 (2H, d, J = 8.0 Hz), 7.89 (1H, br s), 8.01 (1H, dd, J = 2.4, 1.2 Hz), 8.18 (1H, br s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.2 Hz), DMSO: 397 (M + H)⁺FAB 354 1.08-1.33 (2H, m), 1.44-1.58 (1H, m), 1.52-1.64 (2H, m), 1.73-1.88 (2H, m), 2.67 (2H, dd, J = 7.8, 7.8 Hz), 2.80-2.96 (1H, m), 2.92 (3H, s), 2.95 (3H, s), 2.96-3.12 (1H, m), 3.92-4.08 (1H, m), 4.09-4.25 (1H, m), 7.27 (2H, d, J = 7.6 Hz), 7.32 (2H, d, J = 7.6 Hz), 7.67 (1H, br s), 8.01 (1H, dd, J = 2.4, 1.6 Hz), 8.18 (1H, br s), 8.56 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 1.6 Hz), DMSO: 425 (M + H)⁺FAB 355 1.11-1.31 (2H, m), 1.40-1.66 (9H, m), 1.74-1.86 (2H, br), 2.64-2.69 (2H, m), 2.86 (1H, br), 3.02 (1H, br), 3.23-3.38 (2H, m), 3.51-3.64 (2H, m), 4.01 (1H, m), 4.17 (1H, m), 7.15-7.20 (2H, m), 7.30-7.37 (2H, m), 7.67 (1H, s), 8.01 (1H, m), 8.18 (1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 465 (M + H)⁺ESI 356 1.21-1.36 (2H, m), 1.54-1.59 (3H, m), 1.78-1.82 (2H, br), 2.64-2.69 (2H, br), 2.87 (1H, m), 3.03 (1H, m), 3.37-3.69 (8H, br), 3.99 (1H, m), 4.16 (1H, m), 7.15-7.20 (2H, m), 7.30-7.37 (2H, m), 7.67 (1H, s), 8.01 (1H, m), 8.18 (1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 467 (M + H)⁺ESI 357 1.15-1.28 (2H, m), 1.44-1.62 (9H, m), 1.79-1.83 (2H, br), 2.65-2.68 (2H, m), 2.88 (1H, br), 3.03 (1H, br), 3.24-3.37 (2H, br), 3.47-3.62 (2H, m), 4.01 (1H, m), 4.18 (1H, m), 7.26-7.30 (4H, m), 7.67 (1H, s), 8.02 (1H, m), 8.18 (1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 465 (M + H)⁺FAB 358 1.13-1.28 (2H, m), 1.48-1.61 (3H, m), 1.79-1.82 (2H, br), 2.65-2.69 (2H, br), 2.88 (1H, m), 3.04 (1H, m), 3.34-3.65 (8H, br), 4.01 (1H, m), 4.18 (1H, m), 7.15-7.20 (2H, m), 7.28-7.34 (4H, m), 7.66 (1H, s), 8.01 (1H, m), 8.17 (1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 467 (M + H)⁺FAB 359 1.16-1.25 (2H, m), 1.51-1.61 (3H, m), 1.79-1.88 (6H, br), 2.65-2.69 (2H, m), 2.87 (1H, br), 3.03 (1H, br), 3.31-3.38 (2H, br), 3.44-3.47 (2H, m), 4.01 (1H, m), 4.18 (1H, m), 7.29-7.36 (4H, m), 7.68 (1H, s), 8.01 (1H, m), 8.19 (1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 451 (M + H)⁺ESI 360 1.03-1.31 (8H, m), 1.46-1.66 (3H, m), 1.78-1.83 (2H, br), 2.64-2.69 (2H, m), 2.87 (1H, br), 3.03 (1H, br), 3.14-3.24 (2H, br), 3.35-3.49 (2H, m), 4.03 (1H, m), 4.18 (1H, m), 7.12-7.18 (2H, m), 7.27-7.37 (2H, m), 7.68 (1H, s), 8.02 (1H, m), 8.19 (1H, s), 8.56 (1H, m), 8.89 (1H, m), DMSO: 453 (M + H)⁺ESI 361 1.13-1.30 (2H, m), 1.48-1.61 (3H, m), 1.78-1.83 (2H, br), 2.65-2.71 (2H, m), 2.87 (1H, br), 3.03 (1H, br), 3.92-3.98 (2H, m), 4.00 (1H, m), 4.18 (1H, m), 4.37-4.43 (2H, m), 7.38-7.41 (2H, m), 7.66-7.70 (2H, m), 7.73 (1H, s), 8.01 (1H, m), 8.19 (1H, s), 8.56 (1H, m), 8.89 (1H, m), DMSO: 423 (M + H)⁺API 362 1.04-1.37 (8H, m), 1.45-1.68 (3H, m), 1.83 (2H, d, J = 12.8 Hz), 2.69 (2H, t, J = 7.3 Hz), 2.86 (1H, t, J = 12.1 Hz), 2.99 (1H, t, J = 12.1 Hz), 3.28 (2H, br), 3.53 (2H, br), 4.15-4.34 (2H, m), 7.20 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 8.01 (1H, s), 8.59 (1H, s), 8.89 (1H, s)CDCl3: 453 (M + H)⁺ESI 363 1.18-1.36 (2H, m), 1.44-1.68 (3H, m), 1.76-2.12 (6H, m), 2.69 (2H, t, J = 7.5 Hz), 2.84 (2H, t, J = 11.9 Hz), 2.98 (2H, t, J = 11.9 Hz), 4.25 (4H, br), 6.02 (1H, br), 6.73 (1H, br), 7.20 (2H, d, J = 7.9 Hz), 7.45 (2H, d, J = 7.9 Hz), 7.98 (1H, s), 8.57 (1H, s), 8.85 (1H, s)CDCl3: 451 (M + H)⁺ESI

TABLE 59 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 364 1.18-1.36 (2H, m), 1.44-1.70 (3H, m), 1.77-1.92 (2H, m), 2.72 (2H, t, J = 7.5 Hz), 2.85 (2H, t, J = 11.4 Hz), 2.99 (2H, t, J = 11.4 Hz), 4.08 (2H, t, J = 9.6 Hz), 4.26 (2H, br), 4.47 (2H, t, J = 9.6 Hz), 7.25 (2H, d, J = 7.8 Hz), 7.91 (2H, d, J = 7.8 Hz), 7.94-7.99 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 8.83 (1H, d, J = 2.4 Hz)CDCl3: 423 (M + H)⁺ESI 365 1.03 (2H, d, J = 6.2 Hz), 1.12-1.30 (2H, m), 1.48-1.62 (3H, m), 1.80 (2H, d, J = 12.8 Hz), 2.68 (2H, t, J = 7.4 Hz), 2.87 (1H, t, J = 12.8 Hz), 3.03 (1H, t, J = 12.8 Hz), 3.38-3.80 (6H, m), 4.01 (1H, d, J = 12.8 Hz), 4.17 (1H, d, J = 12.8 Hz), 6.65-6.68 (1H, m), 6.84 (1H, d, J = 8.4 Hz), 7.23-7.39 (4H, m), 7.53-7.57 (1H, m), 7.66 (1H, s), 8.00-8.02 (1H, m), 8.11-8.13 (1H, m), 8.18 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.88 (1H, d, J = 2.0 Hz), DMSO: 543 (M + H)⁺FAB 366 1.03 (2H, d, J = 6.2 Hz), 1.12-1.30 (2H, m), 1.48-1.62 (3H, m), 1.80 (2H, d, J = 12.4 Hz), 2.68 (2H, t, J = 7.4 Hz), 2.87 (1H, t, J = 12.4 Hz), 3.03 (1H, t, J = 12.4 Hz), 3.10-3.28 (3H, m), 3.40-3.83 (3H, m), 4.02 (1H, d, J = 12.4 Hz), 4.18 (1H, d, J = 12.4 Hz), 6.80 (1H, t, J = 7.6 Hz), 6.95 (2H, d, J = 7.6 Hz), 7.20-740 (6H, m), 7.66 (1H, s), 8.00 (1H, t, J = 2.4 Hz), 8.18 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.88 (1H, d, J = 2.0 Hz), DMSO: 542 (M + H)⁺FAB 367 1.12-1.32 (2H, m), 1.48-1.63 (3H, m), 1.82 (2H, d, J = 12.4 Hz), 2.68 (2H, t, J = 7.2 Hz), 2.88 (1H, t, J = 12.4 Hz), 3.04 (1H, t, J = 12.4 Hz), 3.40-3.75 (8H, m), 4.02 (1H, d, J = 12.4 Hz), 4.18 (1H, d, J = 12.4 Hz), 6.65-6.68 (1H, m), 6.84 (1H, d, J = 8.8 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.36 (2H, d, J = 8.0 Hz), 7.53-7.57 (1H, m), 7.66 (1H, s), 8.01 (1H, d, J = 2.4 Hz), 8.11-8.13 (1H, m), 8.18 (1H, s), 8.55 (1H, d, J = 2.8 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 543 (M + H)⁺FAB 368 1.11-1.31 (2H, m), 1.48-1.63 (3H, m), 1.81 (2H, d, J = 12.2 Hz), 2.68 (2H, t, J = 7.2 Hz), 2.88 (1H, t, J = 12.8 Hz), 3.04 (1H, t, J = 12.8 Hz), 3.10-3.25 (4H, m), 3.42-3.81 (4H, m), 4.02 (1H, d, J = 12.8 Hz), 4.18 (1H, d, J = 12.8 Hz), 6.81 (1H, t, J = 7.2 Hz), 6.95 (2H, d, J = 8.4 Hz), 7.21-7.37 (6H, m), 7.66 (1H, s), 8.01 (1H, s), 8.18 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.88 (1H, s), DMSO: 542 (M + H)⁺FAB 369 1.19-1.23 (2H, m), 1.52-1.62 (3H, m), 1.78-1.85 (2H, m), 2.70 (2H, d, J = 7.8 Hz), 2.88 (1H, t, J = 11.9 Hz), 3.03 (1H, t, J = 10.7 Hz), 3.52 (2H, dd, J = 5.4, 5.2 Hz), 3.59 (1H, dd, J = 5.3, 5.3 Hz), 4.02 (1H, m), 4.18 (1H, m), 4.48 (1H, t, J = 5.2 Hz), 4.60 (1H, t, J = 5.2 Hz), 7.35-7.38 (2H, m), 7.68-7.69 (2H, m), 7.72-7.75 (1H, m), 8.02-8.07 (1H, m), 8.18-8.23 (1H, m), 8.56-8.59 (1H, m), 8.63-8.68 (1H, m), 8.89-8.91 (1H, m), DMSO: 443 (M + H)⁺FAB 370 1.13-1.33 (2H, m), 1.52-1.63 (3H, m), 1.75-1.85 (2H, m), 2.68 (2H, d, J = 7.8 Hz), 2.88 (1H, t, J = 10.0 Hz), 3.03 (1H, t, J = 10.0 Hz), 3.30-3.35 (2H, m), 3.46-3.54 (2H, m), 4.15 (1H, d, J = 17.2 Hz), 4.18 (1H, d, J = 16.0 Hz), 7.33-7.39 (2H, m), 7.62-7.72 (3H, m), 8.00-8.01 (1H, m), 8.16-8.18 (1H, m), 8.35-8.29 (1H, m), 8.55 (1H, d, J = 3.4 Hz), 8.89 (1H, d, J = 2.2 Hz), DMSO: 441 (M + H)⁺ESI 371 1.21-1.35 (2H, m), 1.48 (9H, s), 1.48-1.60 (1H, m), 1.61-1.69 (2H, m), 1.79-1.87 (2H, m), 2.71 (2H, dd, J = 6.0, 6.0 Hz), 2.86 (1H, t, J = 9.6 Hz), 3.00 (1H, t, J = 9.6 Hz), 4.18-4.33 (2H, m), 5.76 (1H, br), 5.93 (1H, s), 6.28 (1H, br), 7.27-7.35 (2H, m), 7.45-7.50 (1H, m), 7.61 (1H, s), 7.96 (1H, s), 8.58 (1H, s), 8.84 (1H, s)CDCl3: 454 (M + H)⁺ESI 372 1.27 (6H, d, J = 4.8 Hz), 1.61-1.69 (2H, m), 1.72-1.88 (5H, m), 2.71 (2H, t, J = 6.0, 6.0 Hz), 2.86 (1H, t, J = 9.0 Hz), 3.00 (1H, t, J = 9.0 Hz), 4.17-4.36 (3H, m), 5.81 (1H, br), 5.95 (1H, br), 6.54 (1H, br), 7.21-7.39 (2H, m), 7.52 (1H, d, J = 6.0 Hz), 7.63 (1H, s), 7.97 (1H, s), 8.61 (1H, s), 8.89 (1H, s)CDCl3: 439 (M + H)⁺ESI 373 1.10-1.31 (2H, m), 1.47-1.62 (3H, m), 1.78-1.83 (2H, m), 2.39-2.51 (2H, m), 2.66-2.69 (2H, m), 2.82-2.92 (1H, br), 2.98-3.10 (1H, br), 3.65-3.73 (2H, br), 3.89 (2H, t, J = 13.1 Hz), 3.98-4.22 (2H, m), 7.31 (2H, d, J = 8.2 Hz), 7.48 (2H, d, J = 8.2 Hz), 7.63-7.69 (1H, br), 8.00-8.02 (1H, m), 8.15-8.21 (1H, br), 8.55-8.56 (1H, m), 8.88-8.89 (1H, m), DMSO: 487 (M + H)⁺FAB

TABLE 60 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 374 1.10-1.31 (2H, m), 1.47-1.59 (3H, m), 1.77-1.83 (2H, m), 2.56 (2H, t, J = 7.5 Hz), 2.82-3.08 (2H, m), 3.99-4.21 (2H, m), 5.77-5.82 (2H, br), 6.75 (1H, d, J = 7.5 Hz), 7.11 (1H, t, J = 7.5 Hz), 7.17-7.20 (1H, m), 7.25-7.27 (1H, br), 7.65-7.70 (1H, br), 8.00-8.03 (1H, m), 8.15-8.21 (1H, br), 8.40-8.45 (1H, br), 8.54-8.56 (1H, m), 8.88-8.90 (1H, m), DMSO: 412 (M + H)⁺FAB 375 1.10-1.30 (2H, m), 1.46-1.60 (3H, m), 1.76-1.90 (6H, m), 2.57 (2H, t, J = 7.4 Hz), 2.82-3.10 (2H, m), 3.32-3.39 (4H, m), 3.97-4.23 (2H, m), 6.77 (1H, d, J = 7.8), 7.12 (1H, t, J = 7.8 Hz), 7.30-7.38 (2H, m), 7.64-7.68 (1H, br), 7.99-8.02 (2H, m), 8.16-8.21 (1H, br), 8.54-8.56 (1H, m), 8.88-8.90 (1H, m), DMSO: 466 (M + H)⁺FAB 376 1.12-1.30 (2H, m), 1.47-1.63 (3H, m), 1.77-1.85 (2H, m), 2.39-2.52 (2H, m), 2.69 (2H, t, J = 7.8 Hz), 2.83-3.08 (2H, m), 3.63-3.75 (2H, m), 3.83-3.94 (2H, m), 3.97-4.24 (2H, m), 7.33-7.41 (4H, m), 7.66-7.70 (1H, br), 8.03-8.05 (1H, m), 8.18-8.22 (1H, br), 8.57 (1H, d, J = 2.4 Hz), 8.90 (1H, d, J = 1.7 Hz), DMSO: 487 (M + H)⁺FAB 377 1.18-1.38 (2H, m), 1.48-1.71 (3H, m), 1.78-1.89 (2H, m), 2.14-2.32 (2H, m), 2.71 (2H, t, J = 7.5 Hz), 2.80-3.24 (6H, m), 3.57-3.83 (2H, m), 4.26 (2H, dd, J = 7.0 Hz), 5.80 (1H, br), 6.51 (1H, br), 7.09 (1H, d, J = 7.5 Hz), 7.22-7.53 (7H, m), 7.60 (1H, d, J = 8.2 Hz), 7.80-7.87 (1H, m), 8.05 (1H, dd, J = 2.0, 2.0 Hz), 8.16-8.25 (1H, m), 8.60 (1H, s), 8.96 (1H, s), DMSO: 593 (M + H)⁺ESI 378 1.00-1.80 (16H, m), 2.27 (3H, s), 2.65-2.74 (2H, m), 2.80-3.10 (2H, m), 3.95-4.32 (4H, m), 6.42 (1H, d, J = 7.6 Hz), 6.56 (1H, d, J = 8.8 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.67 (1H, s), 8.00 (1H, t, J = 2.4 Hz), 8.19 (1H, s), 8.55 (1H, d, J = 2.4 Hz), 8.89 (1H, d, J = 2.0 Hz), DMSO: 466 (M + H)⁺FAB 379 1.11-1.21 (2H, m), 1.27-1.49 (10H, m), 1.74-1.84 (4H, br), 2.83-2.92 (3H, br), 3.05 (1H, br), 3.71-3.75 (2H, br), 4.02 (1H, br), 4.18 (1H, br), 7.34 (1H, m), 7.58 (1H, m), 7.66-7.71 (2H, m), 7.86 (1H, m), 8.00-8.03 (2H, m), 8.07 (1H, m), 8.19 (1H, s), 8.55 (1H, m), 8.89 (1H, m), DMSO: 502 (M + H)⁺FAB 380 1.00-1.82 (16H, m), 2.77-3.10 (4H, m), 3.95-4.23 (2H, m), 4.53 (2H, d, J = 12.0 Hz), 7.15-7.26 (2H, m), 7.45-7.55 (2H, m), 7.62-7.70 (2H, m), 7.95-8.05 (2H, m), 8.20 (1H, s), 8.46 (1H, d, J = 2.8 Hz), 8.89 (1H, d, J = 1.7 Hz), DMSO: 502 (M + H)⁺FAB 381 1.11-1.20 (2H, m), 1.27-1.32 (2H, m), 1.47-1.61 (3H, m), 1.75-1.78 (2H, m), 2.34-2.44 (2H, m), 2.56-2.74 (4H, m), 2.88 (1H, t, J = 12.1 Hz), 3.04 (1H, t, J = 12.5 Hz), 3.23-3.41 (4H, m), 4.01 (1H, d, J = 13.0 Hz), 4.18 (1H, d, J = 12.4 Hz), 7.37 (1H, d, J = 5.6 Hz), 7.57-7.61 (1H, m), 7.68-7.71 (2H, m), 7.87 (1H, d, J = 8.1 Hz), 8.01 (1H, t, J = 2.2 Hz), 8.06-8.10 (2H, m), 8.18 (1H, br), 8.55 (1H, d, J = 2.4 Hz), 8.88 (1H, d, J = 1.8 Hz), DMSO: 503 (M + H)⁺FAB 382 1.15-1.19 (2H, m), 1.27-1.49 (10H, m), 1.74-1.85 (4H, m), 2.70 (2H, m), 2.89 (1H, t, J = 12.4 Hz), 3.04 (1H, t, J = 12.1 Hz), 3.26-3.31 (2H, m), 4.02 (1H, m), 4.18 (1H, d, J = 12.4 Hz), 7.09 (1H, d, J = 14.8 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.46-7.51 (2H, m), 7.55 (1H, d, J = 8.3 Hz), 7.64-7.70 (1H, br), 7.85-7.87 (1H, m), 8.17 (1H, t, J = 2.2 Hz), 8.07-8.09 (1H, m), 8.15-8.21 (1H, br), 8.55 (1H, d, J = 2.8 Hz), 8.89 (1H, d, J = 1.7 Hz), DMSO: 501 (M + H)⁺FAB

TABLE 61 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 383 0.87 (3H, t, J = 6.4 Hz), 1.20-1.46 (8H, m), 1.54-1.72 (2H, m), 1.70 (2H, q, J = 6.4 Hz), 1.81-1.94 (2H, m), 2.54-2.64 (1H, m), 2.85-3.05 (1H, m), 3.05-3.25 (1H, m), 3.91 (2H, t, J = 6.4 Hz), 4.00-4.16 (1H, m), 4.15-4.31 (1H, m), 6.56-6.63 (1H, m), 7.07-7.13 (1H, m), 7.17 (1H, dd, J = 8.0, 8.0 Hz), 7.29-7.36 (1H, m), 7.45 (1H, dd, J = 7.8, 5.2 Hz), 7.59-7.67 (1H, m), 8.40-8.46 (2H, m), 9.90 (1H, s), DMSO: 440 (M + H)⁺FAB 384 0.87 (3H, t, J = 6.4 Hz), 1.20-1.45 (8H, m), 1.55-1.77 (4H, m), 1.80-1.93 (2H, m), 2.52-2.62 (1H, m), 2.88-3.04 (1H, m), 3.04-3.19 (1H, m), 3.90 (2H, t, J = 6.4 Hz), 4.00-4.14 (1H, m), 4.16-4.30 (1H, m), 6.85 (2H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.3, 4.9 Hz), 7.49 (2H, d, J = 9.2 Hz), 7.61-7.66 (1H, m), 8.40-8.45 (2H, m), 9.78 (1H, s), DMSO: 440 (M + H)⁺FAB 385 369 (M + H)⁺FAB 386 480 (M + H)⁺FAB 387 424 (M + H)⁺FAB 388 0.85 (3H, t, J = 7.2 Hz), 1.20-1.32 (6H, m), 1.45-1.58 (2H, m), 1.56-1.78 (2H, m), 1.81-1.94 (2H, m), 2.48-2.54 (2H, m), 2.55-2.66 (1H, m), 2.90-3.05 (1H, m), 3.07-3.21 (1H, m), 4.00-4.15 (1H, m), 4.17-4.32 (1H, m), 7.10 (2H, d, J = 8.0 Hz), 7.50 (2H, d, J = 8.0 Hz), 7.68 (1H, br s), 8.04 (1H, dd, J = 2.8, 2.0 Hz), 8.19 (1H, br), 8.58 (1H, d, J = 2.8 Hz), 8.90 (1H, d, J = 2.0 Hz), 9.86 (1H, br), DMSO: 453 (M + H)⁺FAB 389 1.56-1.74 (2H, br), 1.88-2.04 (2H, br), 2.48-2.53 (3H, m), 3.25-3.55 (2H, br), 3.65-3.92 (2H, br), 4.46-4.55 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.01 (1H, s), 7.15 (1H, dt, J = 2.9, 8.8 Hz), 7.23-7.30 (2H, m), 7.40-7.47 (1H, m), 7.70-8.30 (2H, br), DMSO 390 1.55-1.74 (2H, br), 1.88-2.04 (2H, br), 3.25-3.55 (2H, br), 3.65-3.92 (2H, br), 4.46-4.54 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.01 (1H, s), 7.15 (1H, dt, J = 2.9, 8.8 Hz), 7.23-7.30 (2H, m), 7.40-7.47 (2H, m), 7.86-7.94 (1H, br), 7.97-8.05 (1H, br), 10.19 (1H, s), DMSO: 439 (M + H)⁺FAB 391 1.58-1.77 (2H, br), 1.91-2.06 (2H, br), 3.28-3.41 (1H, br), 3.45-3.57 (1H, br), 3.65-3.78 (1H, br), 3.82-3.94 (1H, br), 4.48-4.57 (1H, m), 5.07 (2H, s), 6.95 (4H, s), 7.11-7.18 (1H, m), 7.23-7.30 (2H, m), 7.40-7.47 (1H, m), 8.29-8.32 (1H, m), 8.78 (1H, d, J = 2.5 Hz), 8.91 (1H, d, J = 2.0 Hz), DMSO: 448 (M + H)⁺FAB 392 0.78-0.93 (2H, m), 1.04-1.26 (6H, m), 1.35-1.45 (2H, m), 1.54-1.74 (9H, m), 1.90-2.04 (2H, br), 3.28-3.55 (2H, m), 3.66-3.95 (4H, m), 4.46-4.54 (1H, m), 6.84 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 4.8, 8.4 Hz), 7.60-7.66 (1H, m), 8.41-8.45 (2H, m), DMSO: 453 (M + H)⁺FAB 393 415 (M + H)⁺FAB 394 387 (M + H)⁺FAB 395 1.06-1.20 (2H, m), 1.43-1.82 (10H, m), 1.86-2.05 (3H, m), 3.24-3.57 (2H, br), 3.68-3.94 (4H, m) 4.51-4.55 (1H, m), 6.85 (2H, d, J = 9.2 Hz), 6.93 (2H, d, J = 9.2 Hz), 8.08 (1H, dd, J = 1.6, 2.4 Hz), 8.66 (1H, d, J = 2.4 Hz), 8.92 (1H, d, J = 1.6 Hz), 13.38-13.84 (1H, br), DMSO: 455 (M + H)⁺FAB 396 1.21-1.42 (2H, m), 1.78-1.90 (2H, br), 1.93-2.06 (1H, m), 2.85-2.99 (1H, br), 3.01-3.15 (1H, br), 3.81 (2H, d, J = 8.0 Hz), 3.99-4.12 (1H, br), 4.15-4.27 (1H, br), 5.07 (2H, s), 6.88 (2H, d, J = 9.2 Hz), 6.94 (2H, d, J = 9.2 Hz), 7.11-7.18 (1H, m), 7.23-7.29 (2H, m), 7.39-7.47 (2H, m), 7.62 (1H, ddd, J = 1.2, 2.4, 8.0 Hz), 8.40-8.45 (1H, m), DMSO: 437 (M + H)⁺FAB 397 414 (M + H)⁺FAB 398 386 (M + H)⁺FAB 399 1.10-1.33 (2H, m), 1.45-1.61 (3H, m), 1.75-1.87 (2H, br), 2.64 (2H, t, J = 7.6 Hz), 2.80-3.10 (2H, br), 3.95-4.24 (2H, br), 7.12-7.32 (5H, m), 7.90 (2H, d, J = 8.4 Hz), 7.98-8.08 (3H, m), 8.43-8.49 (1H, m), 8.80-8.86 (1H, m), 12.80-13.30 (1H, m),, DMSO: 431 (M + H)⁺FAB

TABLE 62 Ex DAT No. ¹H-NMR δ (ppm), solvent: MS m/z 400 1.06-1.30 (2H, m), 1.56-1.80 (3H, m), 2.47-2.52 (2H, m), 2.76-2.91 (1H, br), 2.93-3.07 (1H, br), 3.92-4.05 (1H, br), 4.08-4.21 (1H, br), 5.10 (2H, s), 6.94 (2H, d, J = 8.0 Hz), 7.08-7.18 (3H, m), 7.24-7.31 (2H, m), 7.40-7.48 (1H, m), 7.71 (1H, dd, J = 4.8, 8.4 Hz), 7.93-7.99 (1H, m), 8.58 (1H, d, J = 4.4 Hz), 8.62-8.78 (1H, m), DMSO: 421 (M + H)⁺FAB 401 1.08-1.31 (2H, m), 1.58-1.79 (3H, m), 2.47-2.52 (2H, m), 2.76-3.05 (2H, br), 3.92-4.22 (2H, br), 5.10 (2H, s), 6.94 (2H, d, J = 8.4 Hz), 7.08-7.19 (3H, m), 7.24-7.31 (2H, m), 7.40-7.48 (1H, m), 7.98-8.03 (1H, m), 8.56-8.62 (1H, m), 8.87-8.93 (1H, br), DMSO: 465 (M + H)⁺FAB 402 1.07-1.28 (2H, br), 1.43-1.60 (3H, m), 1.73-1.82 (2H, br), 2.62 (2H, t, J = 7.8 Hz), 2.77-3.05 (2H, br), 3.92-4.20 (2H, br), 7.00 (1H, dd, J = 2.0, 2.4 Hz), 7.14-7.31 (5H, m), 8.04 (1H, dd, J = 2.0, 2.4 Hz), 7.86-7.94 (1H, br), 7.97-8.03 (1H, br), 10.06-10.26 (1H, br), DMSO: 327 (M + H)⁺FAB 403 351 (M + H)⁺FAB 404 395 (M + H)⁺FAB 405 503 (M + H)⁺FAB 406 453 (M + H)⁺FAB 407 1.02-1.51 (6H, m), 1.68-1.80 (4H, m), 2.28 (3H, s), 2.66-2.74 (2H, m), 2.82-3.09 (2H, m), 3.95-4.31 (4H, m), 6.43 (1H, d, J = 7.1 Hz), 6.56 (1H, d, J = 8.5 Hz), 7.34-7.39 (1H, m), 7.65-7.69 (1H, br), 7.99-8.01 (1H, m), 8.16-8.19 (1H, br), 8.55 (1H, d, J = 2.5 Hz), 8.88 (1H, d, J = 1.9 Hz), DMSO: 452 (M + H)⁺FAB 408 502 (M + H)⁺FAB 409 369 (M + H)⁺FAB 410 327 (M + H)⁺FAB 411 441 (M + H)⁺ESI 412 1.25-1.65 (6H, m), 2.25-2.48 (6H, m), 2.57 (2H, t, J = 7.8 Hz), 3.36-3.64 (4H, m), 7.12-7.30 (5H, m), 7.68 (1H, s), 8.03 (1H, t, J = 2.4 Hz), 8.19 (1H, s), 8.56 (1H, d, J = 2.4 Hz), 8.90 (1H, d, J = 1.5 Hz), DMSO: 397 (M + H)⁺FAB 413 3.00-3.75 (6H, m), 4.01-4.38 (4H, m), 5.17 (2H, s), 7.10 (2H, d, J = 8.8 Hz), 7.13-7.21 (1H, m), 7.27-7.33 (2H, m), 7.42-7.49 (1H, m), 7.59 (2H, d, J = 8.8 Hz), 7.75 (1H, dd, J = 5.2, 7.6 Hz), 7.97-8.02 (1H, m), 8.62 (1H, d, J = 4.4 Hz), 8.70 (1H, d, J = 2.4 Hz), DMSO: 422 (M + H)⁺FAB 414 432 (M + H)⁺FAB 415 431 (M + H)⁺FAB 416 299 (M + H)⁺FAB 417 1.33 (3H, t, J = 6.8 Hz), 1.60-1.76 (2H, br), 1.91-2.07 (2H, br), 3.30-3.43 (1H, br), 3.46-3.60 (1H, br), 3.67-3.75 (1H, br), 3.83-3.96 (1H, br), 4.35 (2H, q, J = 6.8 Hz), 4.47-4.57 (1H, m), 5.07 (2H, s), 6.96 (4H, s), 7.11-7.19 (1H, m), 7.23-7.30 (2H, m), 7.40-7.47 (1H, m), 7.84 (1H, dd, J = 2.4, 8.8 Hz), 8.12 (1H, d, J = 8.8 Hz), 8.58 (1H, d, J = 2.4 Hz), DMSO: 495 (M + H)⁺FAB 418 1.58-1.77 (2H, br), 1.90-2.08 (2H, br), 3.28-3.60 (2H, br), 3.66-3.98 (2H, br), 4.47-4.54 (1H, m), 5.07 (2H, s), 6.96 (4H, s), 7.10-7.19 (1H, m), 7.21-7.32 (2H, m), 7.38-7.49 (1H, m), 7.69-7.77 (1H, m), 8.04 (1H, d, J = 8.6 Hz), 8.60-8.70 (1H, m), DMSO: 467 (M + H)⁺FAB 419 327 (M + H)⁺FAB 420 354 (M + H)⁺FAB 421 437 (M + H)⁺FAB 422 437 (M + H)⁺FAB 423 368 (M + H)⁺FAB

TABLE 63 DAT Ex ¹H-NMR δ (ppm), No. solvent: MS m/z 424 369 (M + H)⁺ESI 425 370 (M + H)⁺FAB 426 383 (M + H)⁺ESI 427 412 (M + H)⁺FAB 428 483 (M + H)⁺FAB 429 384 (M + H)⁺FAB 430 483 (M + H)⁺ESI 431 493 (M + H)⁺ESI 432 522 (M + H)⁺ESI 433 466 (M + H)⁺FAB 434 480 (M + H)⁺ESI 435 438 (M + H)⁺ESI 436 427 (M + H)⁺ESI 437 481 (M + H)⁺FAB

TABLE 64 Ex cell No. FAAH IC₅₀ (nM) 002 0.11 003 0.073 009 0.67 010 0.10 013 0.27 014 0.20 015 0.033 017 0.18 018 0.35 019 0.072 021 0.23 023 0.040 030 0.19 033 0.077 034 0.046 036 0.044 037 0.69 038 0.028 039 0.30 042 0.43 043 0.21 044 0.095 046 0.41 047 0.13 049 0.10 051 0.26 053 0.063 055 0.44 061 0.35 063 0.12 065 0.41 066 0.057 069 0.095 070 0.099 077 0.071 078 0.081 080 0.044 081 0.012 088 0.37 085 0.44 098 0.26 099 0.099 100 0.035 101 0.078 103 0.092 104 0.066 108 0.052 113 0.056 115 0.052 116 0.078 122 0.15 124 0.35 126 0.58 138 0.078 144 0.093 147 0.28 149 0.45 151 0.17 152 0.18 154 0.17 155 0.061 159 0.23 160 0.51 173 0.69 174 0.60 175 0.37 176 0.84 179 0.060 197 0.11 199 0.58 200 0.30 206 0.17 207 0.31 208 0.13 218 0.44 225 0.89 228 0.22 261 0.54 263 0.036 266 0.31 268 0.15 269 0.081 270 0.17 272 0.48 274 0.37 281 0.082 283 0.43 284 0.36 285 0.47 287 0.031 289 0.16 292 0.65 293 0.24 294 0.60 300 0.43 301 0.40 302 0.17 303 0.12 304 0.24 313 0.89 315 0.51 318 0.062 319 0.24 320 0.081 321 0.040 322 0.058 323 0.085 324 0.50 325 0.54 326 0.13 327 0.12 328 0.42 329 0.39 330 0.53 333 0.43 334 0.048 335 0.075 338 0.034 339 0.12 340 0.052 341 0.078 342 0.33 344 0.13 345 0.18 346 0.27 349 0.054 351 0.13 359 0.52 362 0.42 364 0.14 371 0.21 372 0.49 373 0.49 376 0.21 378 0.20 380 0.35

TABLE 65

Com No R¹ R⁴  1 HO₂C(CH₂)₃ H  2 Mo4(CH₂)₂NHCO(CH₂)₃ H  3 4-HexOPh(CH₂)₂NHCO CO₂H  4 4-OctPhNHCO CO₂H  5 Ph(CH₂)₂CONH CO₂Me  6 Ph(CH₂)₂CONH H  7 Ph(CH₂)₂CONH CO₂H  8 Ph(CH₂)₄NHCO CO₂H  9 4-BuPhNHCO CO₂H 10 4-HexPhNHCO CO₂H 11 Py2(CH₂)₂NHCO H 12 Py3(CH₂)₂NHCO H 13 Ph(CH₂)₄NHCO CONH₂ 14 4-BuPhNHCO CONH₂ 15 Ph(CH₂)₃O(CH₂)₂ CO₂H 16 2-H₂NCOPhO(CH₂)₃ CO₂H 17 4-(3-FPhCH₂O)PhO

18 Ph(CH₂)₂

19 1-MeBenzIM 2 (CH₂)₃ CO₂H 20 Ph(CH₂)₂ CO₂Me 21 3-PIPE1Ph(CH₂)₂ CO₂H 22

CO₂H 23 Mo4CH₂ H 24 Mo4(CH₂)₂ CO₂Me 25 4-(3-FPhCH₂)PIPERA1(CH₂)₂ CO₂Me 26 Mo4(CH₂)₃ CO₂Me 27 4-(3-FPhCH₂PIPERA1(CH₂)₂ H 28 Mo(CH₂)₃ H 29 cPen(CH₂)₂ H 30 cPen(CH₂)₂ CO₂Me 31 cPen(CH₂)₂ CO₂H 32 cPen(CH₂)₂ CONH₂ 33 cHexCH₂ H 34 cHexCH₂ CO₂Me 35 cHexCH₂ CO₂H 36 cHexCH₂ CONH₂ 37 cHex(CH₂)₃ H 38 cHex(CH₂)₃ CO₂Me 39 cHex(CH₂)₃ CO₂H 40 cHex(CH₂)₃ CONH₂ 41 Ph(CH₂)₃ H 42 Ph(CH₂)₃ CONH₂ 43 3-FPh(CH₂)₃ H 44 3-FPh(CH₂)₃ CO₂Me 45 3-FPh(CH₂)₃ CO₂H 46 3-FPh(CH₂)₃ CONH₂ 47 3-ClPh(CH₂)₃ H 48 3-ClPh(CH₂)₃ CO₂Me 49 3-ClPh(CH₂)₃ CO₂H 50 3-ClPh(CH₂)₃ CONH₂ 51 3-NCPh(CH₂)₃ H 52 3-NCPh(CH₂)₃ CO₂Me 53 3-NCPh(CH₂)₃ CO₂H 54 3-NCPh(CH₂)₃ CONH₂ 55 3-MeOPh(CH₂)₃ H 56 3-MeOPh(CH₂)₃ CO₂Me 57 3-MeOPh(CH₂)₃ CO₂H 58 3-MeOPh(CH₂)₃ CONH₂ 59 4-FPh(CH₂)₃ H 60 4-FPh(CH₂)₃ CO₂Me 61 4-FPh(CH₂)₃ CO₂H 62 4-FPh(CH₂)₃ CONH₂

TABLE 66

Com No R¹ R⁴  63 4-ClPh(CH₂)₃ H  64 4-ClPh(CH₂)₃ CO₂Me  65 4-ClPh(CH₂)₃ CO₂H  66 4-ClPh(CH₂)₃ CONH₂  67 4-NCPh(CH₂)₃ H  68 4-NCPh(CH₂)₃ CO₂Me  69 4-NCPh(CH₂)₃ CO₂H  70 4-NCPh(CH₂)₃ CONH₂  71 4-MeOPh(CH₂)₃ H  72 4-MeOPh(CH₂)₃ CO₂Me  73 4-MeOPh(CH₂)₃ CO₂H  74 4-MeOPh(CH₂)₃ CONH₂  75 2-FPh(CH₂)₃ H  76 2-FPh(CH₂)₃ CO₂Me  77 2-FPh(CH₂)₃ CO₂H  78 2-FPh(CH₂)₃ CONH₂  79 2-ClPh(CH₂)₃ H  80 2-ClPh(CH₂)₃ CO₂Me  81 2-ClPh(CH₂)₃ CO₂H  82 2-ClPh(CH₂)₃ CONH₂  83 2-NCPh(CH₂)₃ H  84 2-NCPh(CH₂)₃ CO₂Me  85 2-NCPh(CH₂)₃ CO₂H  86 2-NCPh(CH₂)₃ CONH₂  87 2-MeOPh(CH₂)₃ H  88 2-MeOPh(CH₂)₃ CO₂Me  89 2-MeOPh(CH₂)₃ CO₂H  90 2-MeOPh(CH₂)₃ CONH₂  91 3,4-diFPh(CH₂)₃ H  92 3,4-diFPh(CH₂)₃ CO₂Me  93 3,4-diFPh(CH₂)₃ CO₂H  94 3,4-diFPh(CH₂)₃ CONH₂  95 3,5-diFPh(CH₂)₃ H  96 3,5-diFPh(CH₂)₃ CO₂Me  97 3,5-diFPh(CH₂)₃ CO₂H  98 3,5-diFPh(CH₂)₃ CONH₂  99 2,5-diFPh(CH₂)₃ H 100 2,5-diFPh(CH₂)₃ CO₂Me 101 2,5-diFPh(CH₂)₃ CO₂H 102 2,5-diFPh(CH₂)₃ CONH₂ 103 3-NC-5-FPh(CH₂)₃ H 104 3-NC-5-FPh(CH₂)₃ CO₂Me 105 3-NC-5-FPh(CH₂)₃ CO₂H 106 3-NC-5-FPh(CH₂)₃ CONH₂ 107 3-FPh(CH₂)₂ H 108 3-ClPh(CH₂)₂ H 109 3-NCPh(CH₂)₂ H 110 3-MeOPh(CH₂)₂ H 111 3-H₂NCOPh(CH₂)₂ H 112 3-Me₂NCOPh(CH₂)₂ H 113 3-PIPE1COPh(CH₂)₂ H 114 3-PYRR1COPh(CH₂)₂ H 115 3-EtNHCOPh(CH₂)₂ H 116 3-Et₂NCOPh(CH₂)₂ H 117 3-cHexNHCOPh(CH₂)₂ H 118 4-FPh(CH₂)₂ H 119 4-ClPh(CH₂)₂ H 120 4-NCPh(CH₂)₂ H 121 4-MeOPh(CH₂)₂ H 122 4-Me₂NCOPh(CH₂)₂ H 123 4-PIPE1COPh(CH₂)₂ H 124 4-PYRR1COPh(CH₂)₂ H 125 4-EtNHCOPh(CH₂)₂ H 126 4-Et₂NCOPh(CH₂)₂ H

TABLE 67

Com No R¹ R⁴ 127 4-cHexNHCOPh(CH₂)₂ H 128 2-FPh(CH₂)₂ H 129 2-ClPh(CH₂)₂ H 130 2-NCPh(CH₂)₂ H 131 2-MeOPh(CH₂)₂ H 132 3,4-diFPh(CH₂)₂ H 133 3,4-diFPh(CH₂)₂ CO₂Me 134 3,4-diFPh(CH₂)₂ CO₂H 135 3,4-diFPh(CH₂)₂ CONH₂ 136 3,5-diFPh(CH₂)₂ H 137 3,5-diFPh(CH₂)₂ CO₂Me 138 3,5-diFPh(CH₂)₂ CO₂H 139 3,5-diFPh(CH₂)₂ CONH₂ 140 2,5-diFPh(CH₂)₂ H 141 2,5-diFPh(CH₂)₂ CO₂Me 142 2,5-diFPh(CH₂)₂ CO₂H 143 2,5-diFPh(CH₂)₂ CONH₂ 144 3-Cl-4-FPh(CH₂)₂ H 145 3-Cl-4-FPh(CH₂)₂ CO₂Me 146 3-Cl-4-FPh(CH₂)₂ CO₂H 147 3-Cl-4-FPh(CH₂)₂ CONH₂ 148 3-Cl-5-FPh(CH₂)₂ H 149 3-Cl-5-FPh(CH₂)₂ CO₂Me 150 3-Cl-5-FPh(CH₂)₂ CO₂H 151 3-Cl-5-FPh(CH₂)₂ CONH₂ 152 2-F-5-ClPh(CH₂)₂ H 153 2-F-5-ClPh(CH₂)₂ CO₂Me 154 2-F-5-ClPh(CH₂)₂ CO₂H 155 2-F-5-ClPh(CH₂)₂ CONH₂ 156 3-MeO-4-FPh(CH₂)₂ H 157 3-MeO-4-FPh(CH₂)₂ CO₂Me 158 3-MeO-4-FPh(CH₂)₂ CO₂H 159 3-MeO-4-FPh(CH₂)₂ CONH₂ 160 3-F-5-MeOPh(CH₂)₂ H 161 3-F-5-MeOPh(CH₂)₂ CO₂Me 162 3-F-5-MeOPh(CH₂)₂ CO₂H 163 3-F-5-MeOPh(CH₂)₂ CONH₂ 164 2-F-5-MeOPh(CH₂)₂ H 165 2-F-5-MeOPh(CH₂)₂ CO₂Me 166 2-F-5-MeOPh(CH₂)₂ CO₂H 167 2-F-5-MeOPh(CH₂)₂ CONH₂ 168 2,4-diFPh(CH₂)₂ H 169 2,4-diFPh(CH₂)₂ CO₂Me 170 2,4-diFPh(CH₂)₂ CO₂H 171 2,4-diFPh(CH₂)₂ CONH₂ 172 2-F-4-ClPh(CH₂)₂ H 173 2-F-4-ClPh(CH₂)₂ CO₂Me 174 2-F-4-ClPh(CH₂)₂ CO₂H 175 2-F-4-ClPh(CH₂)₂ CONH₂ 176 2-F-4-NCPh(CH₂)₂ H 177 2-F-4-NCPh(CH₂)₂ CO₂Me 178 2-F-4-NCPh(CH₂)₂ CO₂H 179 2-F-4-NCPh(CH₂)₂ CONH₂ 180 2-F-4-MeOPh(CH₂)₂ H 181 2-F-4-MeOPh(CH₂)₂ CO₂Me 182 2-F-4-MeOPh(CH₂)₂ CO₂H 183 2-F-4-MeOPh(CH₂)₂ CONH₂ 184 BIP3(CH₂)₂ H 185 3′-FBIP3(CH₂)₂ H 186 3′-NCBIP3(CH₂)₂ H 187 3′-MeOBIP3(CH₂)₂ H 188 3′,4′-diFBIP3(CH₂)₂ H 189 3′-MeO-4′-FBIP3(CH₂)₂ H 190 BIP4(CH₂)₂ H 191 3′-FBIP4(CH₂)₂ H 192 3′-NCBIP4(CH₂)₂ H

TABLE 68

Com No R¹ R⁴ 193 3′-MeOBIP4(CH₂)₂ H 194 3′,4′-diFBIP4(CH₂)₂ H 195 3′-MeO-4′-FBIP4(CH₂)₂ H 196 3-Py2Ph(CH₂)₂ H 197 3-MeOPhNHCO H 198 4-MeOPhNHCO H 199 3-MeO-4-FPhNHCO H 200 3-F-5-MeOPhNHCO H 201 2-F-5-MeOPhNHCO H 202 3-F-4-MeOPhNHCO H 203 2-F-4-MeOPhNHCO H 204 1-(6-MePy2)PIPE4(CH₂)₃ H 205 1-(6-MePy2)PIPE4CH₂ H 206 1-PhCOPIPE4(CH₂)₃ H 207 1-(6-MePy2)PIPE4(CH₂)₂ H 208 1-(6-MePy2)PIPERA4(CH₂)₃ H 209 1-QUI2PIPE4(CH₂)₃ H 210 1-ISOQUI1PIPE4(CH₂)₃ H 211 1-ISOQUI1PIPERA4(CH₂)₃ H 212 1-NAPH1PIPE4(CH₂)₃ H 213

H 214

CONH₂

TABLE 69

Com No R¹ R⁴ 215 Ph(CH₂)₄ CO₂H 216 Ph CO₂H 217 Ph(CH₂)₃ CONH(CH₂)₂OH 218 Ph(CH₂)₅ CO₂H 219 cHex(CH₂)₂ H 220 Ph(CH₂)₄ H 221 Ph(CH₂)₃ H 222 3-MePh(CH₂)₂ H 223 3-MeOPh(CH₂)₂ H 224 3-FPh(CH₂)₂ H 225 3-NCPh(CH₂)₂ H 226 4-MePh(CH₂)₂ H 227 4-MeOPh(CH₂)₂ H 228 4-FPh(CH₂)₂ H 229 4-NCPh(CH₂)₂ H 230 2-MePh(CH₂)₂ H 231 2-MeOPh(CH₂)₂ H 232 2-FPh(CH₂)₂ H 233 2-NCPh(CH₂)₂ H 234 3-Me-4-FPh(CH₂)₂ H 235 3-F-5-MePh(CH₂)₂ H 236 2-F-5-MePh(CH₂)₂ H 237 3-MeO-4-FPh(CH₂)₂ H 238 3-F-5-MeOPh(CH₂)₂ H 239 2-F-5-MeOPh(CH₂)₂ H 240 3,4-diFPh(CH₂)₂ H 241 3,5-diFPh(CH₂)₂ H 242 2,5-diFPh(CH₂)₂ H 243 3-iPrOPh(CH₂)₂ H 244 3-NC-4-FPh(CH₂)₂ H 245 4-tBucHex(CH₂)₂ H 246 3-H₂NCOPh(CH₂)₂ H 247 1-(6-MePy2)PIPE4(CH₂)₃ H 248 3-cHexCH₂OPhCO CONH₂ 249 3-cHex(CH₂)₂OPhCO CONH₂ 250 3-cHepCH₂OPhCO CONH₂ 251 3-PhCH₂OPhCO CONH₂ 252 4-PhCH₂OPhCO CONH₂ 253 3-cOctCH₂OPhCO CONH₂ 254 4-cHexCH₂N(Me)PhCO CONH₂ 255 4-(3-ClPhCH₂O)PhCO CONH₂ 256 4-(3-F₃CPhCH₂O)PhCO CONH₂ 257 4-(3-MeOPhCH₂O)PhCO CONH₂ 258 4-(3-NCPhCH₂O)PhCO CONH₂ 259 4-(3,5-diFPhCH₂O)PhCO CONH₂ 260 4-cHexCH₂OPhCO CONH₂ 261 PhCH₂OCO CONH₂ 262 4-tBuOPhCO CONH₂ 263 4-PhCH₂OPhCH₂ CONH₂ 264 4-H₂NCOPhOCH₂CO CONH₂ 265 Ph(CH₂)₂OCO CONH₂ 266 3-MePh(CH₂)₂ CONH₂ 267 3-MeOPh(CH₂)₂ CONH₂ 268 3-FPh(CH₂)₂ CONH₂ 269 3-NCPh(CH₂)₂ CONH₂ 270 4-MePh(CH₂)₂ CONH₂ 271 4-MeOPh(CH₂)₂ CONH₂ 272 4-FPh(CH₂)₂ CONH₂ 273 4-NCPh(CH₂)₂ CONH₂ 274 2-MePh(CH₂)₂ CONH₂ 275 2-MeOPh(CH₂)₂ CONH₂ 276 2-FPh(CH₂)₂ CONH₂ 277 2-NCPh(CH₂)₂ CONH₂ 278 3-MeO-4-FPh(CH₂)₂ CONH₂ 279 2-F-3-MeOPh(CH₂)₂ CONH₂ 280 2-F-5-MeOPh(CH₂)₂ CONH₂ 281 3-Me-4-FPh(CH₂)₂ CONH₂ 282 3-F-5-MePh(CH₂)₂ CONH₂

TABLE 70

Com No R¹ R⁴ 283 2-F-5-MePh(CH₂)₂ CONH₂ 284 3,4-diFPh(CH₂)₂ CONH₂ 285 3,5-diFPh(CH₂)₂ CONH₂ 286 2,5-diFPh(CH₂)₂ CONH₂ 287 4-tBucHex(CH₂)₂ CONH₂ 288 3-cHexCH₂OPhCO CO₂Me 289 3-cHex(CH₂)₂OPhCO CO₂Me 290 3-cHepCH₂OPhCO CO₂Me 291 3-PhCH₂OPhCO CO₂Me 292 4-PhCH₂OPhCO CO₂Me 293 3-cOctCH₂OPhCO CO₂Me 294 4-[3-FPhCH₂N(Me)]PhCO CO₂Me 295 4-[3,4-diFPhCH₂N(Me)]PhCO CO₂Me 296 4-[3,5-diFPhCH₂N(Me)]PhCO CO₂Me 297 4-[2,5-diFPhCH₂N(Me)]PhCO CO₂Me 298 4-cHexCH₂N(Me)PhCO CO₂Me 299 4-(3-ClPhCH₂O)PhCO CO₂Me 300 4-(3-F₃CPhCH₂O)PhCO CO₂Me 301 4-(3-MeOPhCH₂O)PhCO CO₂Me 302 4-(3-MeO-4-FPhCH₂O)PhCO CO₂Me 303 4-(3-F-5-MeOPhCH₂O)PhCO CO₂Me 304 4-(3-NCPhCH₂O)PhCO CO₂Me 305 4-(3,5-diFPhCH₂O)PhCO CO₂Me 306 4-cHexCH₂OPhCO CO₂Me 307 PhCH₂OCO CO₂Me 308 4-tBuOPhCO CO₂Me 309 4-PhCH₂OPhCH₂ CO₂Me 310 4-H₂NCOPhOCH₂CO CO₂Me 311 Ph(CH₂)₂OCO CO₂Me 312 3-Cl-4-(3-NCPhCH₂O)PhCO CO₂Me 313 2-Cl-4-(3-NCPhCH₂O)PhCO CO₂Me 314 4-[3-FPhCH₂N(Me)]PhCO CO₂H 315 4-cHexCH₂N(Me)PhCO CO₂H 316 4-(3-ClPhCH₂O)PhCO CO₂H 317 3-MePh(CH₂)₂ CO₂Me 318 3-MeOPh(CH₂)₂ CO₂Me 319 3-FPh(CH₂)₂ CO₂Me 320 3-NCPh(CH₂)₂ CO₂Me 321 4-MePh(CH₂)₂ CO₂Me 322 4-MeOPh(CH₂)₂ CO₂Me 323 4-FPh(CH₂)₂ CO₂Me 324 4-NCPh(CH₂)₂ CO₂Me 325 2-MePh(CH₂)₂ CO₂Me 326 2-MeOPh(CH₂)₂ CO₂Me 327 2-FPh(CH₂)₂ CO₂Me 328 2-NCPh(CH₂)₂ CO₂Me 329 3-Me-4-FPh(CH₂)₂ CO₂Me 330 2-F-5-MePh(CH₂)₂ CO₂Me 331 3-F-5-MePh(CH₂)₂ CO₂Me 332 3-MeO-4-FPh(CH₂)₂ CO₂Me 333 2-F-5-MeOPh(CH₂)₂ CO₂Me 334 3-F-5-MeOPh(CH₂)₂ CO₂Me 335 3,4-diFPh(CH₂)₂ CO₂Me 336 2,5-diFPh(CH₂)₂ CO₂Me 337 3,5-diFPh(CH₂)₂ CO₂Me 338 4-tBucHex(CH₂)₂ CO₂Me 339 3-cHexCH₂OPhCO CO₂H 340 3-cHex(CH₂)₂OPhCO CO₂H 341 3-cHepCH₂OPhCO CO₂H 342 3-PhCH₂OPhCO CO₂H 343 4-PhCH₂OPhCO CO₂H 344 3-cOctCH₂OPhCO CO₂H 345 4-(3-F₃CPhCH₂O)PhCO CO₂H 346 4-(3-MeOPhCH₂O)PhCO CO₂H 347 4-(3-NCPhCH₂O)PhCO CO₂H 348 4-(3,5-diFPhCH₂O)PhCO CO₂H 349 4-cHexCH₂OPhCO CO₂H 350 PhCH₂OCO CO₂H

TABLE 71

Com No R¹ R⁴ 351 4-tBuOPhCO CO₂H 352 4-PhCH₂OPhCH₂ CO₂H 353 4-H₂NCOPhOCH₂CO CO₂H 354 Ph(CH₂)₂OCO CO₂H 355 3-Cl-4-(3-NCPhCH₂O)PhCO CO₂H 356 2-Cl-4-(3-NCPhCH₂O)PhCO CO₂H 357 3-MePh(CH₂)₂ CO₂H 358 3-MeOPh(CH₂)₂ CO₂H 359 3-FPh(CH₂)₂ CO₂H 360 3-NCPh(CH₂)₂ CO₂H 361 4-tBucHex(CH₂)₂ CO₂H 362 4-(4-FPhCH₂O)PhCO CONH₂ 363 4-(4-FPhCH₂O)PhCO CO₂Me 364 4-(4-FPhCH₂O)PhCO CO₂H 365 4-(3,4-diFPhCH₂O)PhCO CONH₂ 366 4-(3,4-diFPhCH₂O)PhCO CO₂Me 367 4-(2,4-diFPhCH₂O)PhCO CONH₂ 368 4-(2,4-diFPhCH₂O)PhCO CO₂Me 369 Ph(CH₂)₂ CONH₂ 370 Ph(CH₂)₄ CONH₂ 371 4-[3-FPhCH₂N(Me)]PhCO CONH₂ 372 4-[3,4-diFPhCH₂N(Me)]PhCO CONH₂ 373 4-[3,5-diFPhCH₂N(Me)]PhCO CONH₂ 374 4-[3-MeO-4-FPhCH₂N(Me)]PhCO CONH₂ 375 4-[3-F-5-MeOPhCH₂N(Me)]PhCO CONH₂ 376 3-Cl-4-(3-NCPhCH₂O)PhCO CONH₂ 377 2-Cl-4-(3-NCPhCH₂O)PhCO CONH₂

TABLE 72 Com No Str 378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

TABLE 73 Com No Str 400

401

402

403

404

405

406

INDUSTRIAL APPLICABILITY

The compounds of the present invention have an excellent FAAH-inhibitory activity, and are useful for treatment of FAAH-associated disorders, especially urinary frequency and urinary incontinence, overactive bladder and/or pain.

SEQUENCE LISTING FREE TEXT

The inventor is shown in the numeral entry <223> of SEQ ID NO:1 in the following sequence listing. 

1. A pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of a general formula (III) or its pharmaceutically acceptable salt:

wherein the symbols in formula (III) have the following meanings: ring A represents benzene ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, or 5- to 7-membered nitrogen-containing hetero ring; L represents single bond, lower alkylene, lower alkenylene, —N(R¹⁵)—C(═O)—, —C(═O)—N(R¹⁵)—, -(lower alkenylene)-C(═O)—, —O—, or —C(═O)—; R¹⁵ represents H, or lower alkyl; X represents CH, or N; R⁸, R⁹, and R¹⁰ are the same or different, each representing (i) a group selected from the group consisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; (ii) aryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; (iii) nitrogen-containing heteroaryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; (iv) R¹⁶—(lower alkylene)-O—; (v) R¹⁶—(lower alkylene)-N(R¹⁵)—; or (vi) R¹⁷R¹⁸N—C(═O)—, wherein R¹⁶ represents (i) aryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; (ii) nitrogen-containing heteroaryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; or (iii) 3- to 8-membered cycloalkyl, wherein R¹⁷ and R¹⁸ are the same or different, each representing H, lower alkyl, or 3- to 8-membered cycloalkyl, or R¹⁷ and R¹⁸ may form, together with the N atom bonding thereto, 3- to 8-membered nitrogen-containing hetero ring, R¹¹ represents H, lower alkyl, or oxo (═O), and one of R¹², R¹³ and R¹⁴ is —C(═O)—O-(lower alkyl) or —CO₂H, and the others are H.
 2. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1, wherein the ring A is benzene ring, cyclohexane ring, piperidine ring, or piperazine ring.
 3. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 2, wherein R⁹, R¹⁰, R¹¹, R¹² and R¹³ are H.
 4. A pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of a general formula (IV) or its pharmaceutically acceptable salt:

wherein the symbols in formula (IV) have the following meanings: ring A¹ represents benzene ring, piperidine ring or piperazine ring; L¹ represents lower alkylene, lower alkenylene, —N(R¹⁵)—C(═O)—, or —O—, wherein R¹⁵ represents H, or lower alkyl; R¹⁹ represents (i) a group selected from the group consisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; (ii) nitrogen-containing heteroaryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; (iii) R¹⁶—(lower alkylene)-O—; or (iv) R¹⁷R¹⁸N—C(═O)—; wherein R¹⁶ represents (i) aryl optionally substituted with one the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; (ii) nitrogen-containing heteroaryl optionally substituted with the same or different 1 to 5 groups selected from the group consisting of H, halo, —CN, —CF₃, lower alkyl, and —O-lower alkyl; or (iii) 3- to 8-membered cycloalkyl, wherein R¹⁷ and R¹⁸ are the same or different, each representing H or lower alkyl, or R¹⁷ and R¹⁸ may form, together with the N atom bonding thereto, 5- or 6-membered nitrogen-containing hetero ring, and R²⁰ represents —C(═O)—O-(lower alkyl) or —CO₂H.
 5. A pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of a general formula (V) or its pharmaceutically acceptable salt:

wherein the symbols in formula (V) have the following meanings: L² represents lower alkylene, lower alkenylene, or -(lower alkenylene)-C(═O)—, R²¹ represents H, halo, —CN, —CF₃, lower alkyl, or —O-lower alkyl, and R²² represents —C(═O)—O-(lower alkyl) or —CO₂H.
 6. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1, the compound being one among the following group: 5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}nicotinic acid, 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinic acid, 5-[({4-[4-(2-cyclohexylethoxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid, 5-[({4-[(E)-2-phenylvinyl]piperidin-1-yl}carbonyl)oxy]nicotinic acid, 5-{[(4-[3-[1-(6-methylpyridin-2-yl)piperidin-4-yl]propyl}piperidin-1-yl)carbonyl]oxy}nicotinic acid, and 5-(methoxycarbonyl)pyridin-3-yl 4-(2-phenylethyl)piperazine-1-carboxylate.
 7. A pharmaceutical composition comprising the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt of claim 1 as an active ingredient thereof.
 8. A method for treating urinary frequency, urinary incontinence and/or overactive bladder, comprising administering a therapeutically effective amount of the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of claim 1 or its pharmaceutically acceptable salt to a patient.
 9. A method for treating pain, comprising administering a therapeutically effective amount of the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound of claim 1 or its pharmaceutically acceptable salt to a patient.
 10. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound is 5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}nicotinic acid.
 11. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound is 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinic acid.
 12. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound is 5-[({4-[4-(2-cyclohexylethoxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid.
 13. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound is 54({4-[(E)-2-phenylvinyl]piperidin-1-yl}carbonyl)oxy]nicotinic acid.
 14. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound is 5-{[(4-[3-[1-(6-methylpyridin-2-yl)piperidin-4-yl]propyl}piperidin-1-yl)carbonyl]oxy}nicotinic acid.
 15. The pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound is 5-(methoxycarbonyl)pyridin-3-yl 4-(2-phenylethyl)piperazine-1-carboxylate. 